VCV000042792.74 - ClinVar

NM_000256.3(MYBPC3):c.772G>A (p.Glu258Lys)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(33)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000256.3(MYBPC3):c.772G>A (p.Glu258Lys)

Variation ID: 42792 Accession: VCV000042792.74

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47348424 (GRCh38) [ NCBI UCSC ] 11: 47369975 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Nov 4, 2015	Oct 20, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.772G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Glu258Lys	missense
NC_000011.10:g.47348424C>T
NC_000011.9:g.47369975C>T
NG_007667.1:g.9279G>A
LRG_386:g.9279G>A
LRG_386t1:c.772G>A	LRG_386p1:p.Glu258Lys

... more HGVS ... less HGVS

Protein change

E258K

Other names

p.E258K:GAG>AAG

Canonical SPDI

NC_000011.10:47348423:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00003

Exome Aggregation Consortium (ExAC) 0.00004

The Genome Aggregation Database (gnomAD) 0.00004

Links

dbSNP: rs397516074 ClinGen: CA015823 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MYBPC3		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3960	3979

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Primary familial hypertrophic cardiomyopathy	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Dec 12, 2017	RCV000035668.11
Hypertrophic cardiomyopathy 4	Pathogenic/Likely pathogenic (10)	criteria provided, multiple submitters, no conflicts	Dec 7, 2023	RCV000161125.22
not provided	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	Aug 1, 2023	RCV000158310.36
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Mar 30, 2022	RCV000247227.3
Hypertrophic cardiomyopathy	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000205517.24
Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Sep 21, 2022	RCV000763244.4
Cardiomyopathy	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 30, 2023	RCV001170208.10
Left ventricular noncompaction 10	Pathogenic (1)	no assertion criteria provided	Nov 2, 2021	RCV002290957.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jan 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893880.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (May 14, 2019)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Hypertrophic cardiomyopathy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000059319.6 First in ClinVar: May 03, 2013 Last updated: Jul 04, 2020	Publications: PubMed (19) PubMed: 9562578‚ 15563892‚ 12951062‚ 14563344‚ 16858239‚ 18533079‚ 15114369‚ 20173211‚ 18957093‚ 12974739‚ 20359594‚ 18374358‚ 20031602‚ 17908752‚ 19574547‚ 20159828‚ 12707239‚ 19808356‚ 15519027 Comment: The p.Glu258Lys variant in MYBPC3 has been reported in multiple HCM probands and segregated in many additional affected family members (Girolami 2006, Marston 2009, Niimura … (more) The p.Glu258Lys variant in MYBPC3 has been reported in multiple HCM probands and segregated in many additional affected family members (Girolami 2006, Marston 2009, Niimura 1998, Nanni 2003, Olivotto 2008, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 42792) and has been identified in 4/124374 of European and in 2/23498 of African chromosomes by gnomAD (https://gnomad.broadinstitute.org/). The p.Glu258Lys variant is located in the last base of exon 6, which is part of the 5â€™ splice region. Functional studies using patient RNA have shown that this alteration affects splicing, leading to skipping of exon 6, which is predicted to result in a frameshift, premature termination and therefore likely in a loss of function (Andersen 2004, Martson 2009). Heterozygous loss of function of the MYBPC3 gene is an established disease mechanism in autosomal dominant HCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM based on case observations, segregation with disease, low frequency in the general population and observed impact on splicing. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2_Supporting, PS3_Moderate. (less) Number of individuals with the variant: 67
Pathogenic (Mar 30, 2022)	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000320235.6 First in ClinVar: Oct 02, 2016 Last updated: Nov 29, 2022	Publications: PubMed (4) PubMed: 16858239‚ 25031304‚ 25351510‚ 9562578 Comment: The c.772G>A pathogenic mutation (also known as p.E258K), located in coding exon 6 of the MYBPC3 gene, results from a G to A substitution at … (more) The c.772G>A pathogenic mutation (also known as p.E258K), located in coding exon 6 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 772. The glutamic acid at codon 258 is replaced by lysine, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 6, which makes it likely to have some effect on normal mRNA splicing. In one study, RT-qPCR analysis showed that the altered allele resulted in skipping of exon 6 and all of the mutant transcripts were truncated (Helms AS et al. Circ Cardiovasc Genet. 2014;7(4):434-43). This alteration has been identified in multiple individuals with hypertrophic cardiomyopathy (HCM) with co-segregation and a suggested founder effect (Niimura H et al. N Engl J Med. 1998;338(18):1248-57; Girolami F et al. J Cardiovasc Med (Hagerstown). 2006;7(8):601-7; Bongini C. Am J Cardiol. 2016;117(7):1151-9). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less) Number of individuals with the variant: 1
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hypertrophic cardiomyopathy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000260690.12 First in ClinVar: Jan 31, 2016 Last updated: Feb 14, 2024	Publications: PubMed (14) PubMed: 28492532‚ 9562578‚ 12707239‚ 15563892‚ 18533079‚ 20031602‚ 22267749‚ 23233322‚ 15769446‚ 19590044‚ 23980194‚ 15114369‚ 19574547‚ 25031304 Comment: This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 258 of the MYBPC3 protein … (more) This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 258 of the MYBPC3 protein (p.Glu258Lys). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs397516074, gnomAD 0.009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 9562578, 12707239, 15563892, 18533079, 20031602, 22267749, 23233322). This variant is also known as E264K. ClinVar contains an entry for this variant (Variation ID: 42792). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MYBPC3 function (PMID: 15769446, 19590044, 23980194). Studies have shown that this missense change results in skipping of exon 6 and introduces a premature termination codon (PMID: 15114369, 19574547, 25031304). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Apr 03, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000231501.5 First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MYBPC3 Number of individuals with the variant: 2 Sex: mixed
Pathogenic (Oct 28, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000208245.11 First in ClinVar: Feb 24, 2015 Last updated: Oct 09, 2016	Comment: Reported to segregate with disease in multiple families (Niimura et al., 1998; Richard et al., 2003; Ho et al., 2009; Zhao et al., 2017); Proposed … (more) Reported to segregate with disease in multiple families (Niimura et al., 1998; Richard et al., 2003; Ho et al., 2009; Zhao et al., 2017); Proposed as an Italian founder mutation (Girolami et al., 2006; Olivotto et al., 2008); Observed in 6/272910 global alleles in large population cohorts (Lek et al., 2016); Located in the last nucleotide position of exon 6, which is part of the splice donor site; Functional studies have demonstrated that the E258K variant leads to aberrant gene splicing of exon 6 (Andersen et al., 2004; Vignier et al., 2009; Helms et al., 2014); Additional studies suggest this variant may result in rapid protein degradation (Sarikas et al., 2005; Vignier et al., 2009) or, if abnormal protein is expressed, it may lead to altered protein interaction and contractile kinetics (De Lange et al., 2013); In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID 42792; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26671970, 30550750, 27532257, 23233322, 15114369, 29875424, 30165862, 28687478, 28679633, 30972196, 9562578, 19574547, 20359594, 18533079, 23283745, 22907696, 25031304, 23980194, 12951062, 26914223, 25971843, 21310275, 12707239, 15563892, 15519027, 23527136, 19590044, 15769446, 20031602, 22267749, 16858239, 28450932, 28790153, 29524613, 28916354, 12974739, 18957093, 27574918, 27267291, 27600940, 26869393, 25351510, 29447731, 30645170, 30446606, 31006259, 31737537, 31447099, 33673806, 33297573, 32686758) (less)
Pathogenic (Sep 07, 2015)	criteria provided, single submitter (Variant Classification) Method: clinical testing	Primary familial hypertrophic cardiomyopathy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV000188783.4 First in ClinVar: Sep 07, 2014 Last updated: Sep 22, 2018	Publications: PubMed (6) PubMed: 12707239‚ 12951062‚ 14563344‚ 15519027‚ 15563892‚ 15769446 Number of individuals with the variant: 3
Likely pathogenic (-)	criteria provided, single submitter (LGCM Criteria August 2015) Method: clinical testing	Hypertrophic cardiomyopathy 4 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Laboratory of Genetics and Molecular Cardiology, University of São Paulo Study: Sarcomeric Human Cardiomyopathy Registry (ShaRe) Accession: SCV000256170.1 First in ClinVar: Nov 04, 2015 Last updated: Nov 04, 2015	Publications: PubMed (5) PubMed: 15114369‚ 16858239‚ 12951062‚ 9562578‚ 15563892 Number of individuals with the variant: 2
Pathogenic (Dec 20, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Primary familial hypertrophic cardiomyopathy Affected status: yes Allele origin: germline	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute Accession: SCV000747994.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Pathogenic (Aug 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy 4 Affected status: unknown Allele origin: germline	Phosphorus, Inc. Accession: SCV000679779.1 First in ClinVar: Oct 22, 2016 Last updated: Oct 22, 2016	Publications: PubMed (36) PubMed: 9562578‚ 12707239‚ 12951062‚ 12974739‚ 14563344‚ 15114369‚ 15519027‚ 15563892‚ 15769446‚ 16858239‚ 17908752‚ 18374358‚ 18403758‚ 18414213‚ 18533079‚ 18957093‚ 19574547‚ 19808356‚ 20031602‚ 20159828‚ 20173211‚ 20359594‚ 21835320‚ 22267749‚ 22907696‚ 23054336‚ 23283745‚ 23782526‚ 23980194‚ 24033266‚ 24510615‚ 24793961‚ 25611685‚ 25971843‚ 27532257‚ 397516074 Number of individuals with the variant: 1
Pathogenic (Oct 02, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypertrophic cardiomyopathy 4 Affected status: unknown Allele origin: germline	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine Accession: SCV001434957.1 First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020	Comment: The c.772G>A (p.Glu258Lys) variant in the MYBPC3 gene has been reported in multiple unrelated individuals with hypertrophic cardiomyopathies (PMID: 9562578, 12707239, 15114369, 15563892, 16858239, 18533079, … (more) The c.772G>A (p.Glu258Lys) variant in the MYBPC3 gene has been reported in multiple unrelated individuals with hypertrophic cardiomyopathies (PMID: 9562578, 12707239, 15114369, 15563892, 16858239, 18533079, 23233322, 25031304). This variant has an extremely low frequency in large databases of genetic variation in the general population. mRNA studies demonstrated that this variant resulted in skipping of exon 6 (PMID: 15114369, 25031304). Therefore, this c.772G>A (p.Glu258Lys) variant in the MYBPC3 gene is classified as pathogenic. (less)
Pathogenic (May 09, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy 4 Affected status: yes Allele origin: germline	Center of Genomic medicine, Geneva, University Hospital of Geneva Accession: SCV000693449.2 First in ClinVar: Mar 03, 2018 Last updated: Dec 11, 2022	Age: 30-39 years Sex: female
Pathogenic (Dec 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy 4 (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002587108.2 First in ClinVar: Oct 29, 2022 Last updated: Dec 17, 2023	Comment: Criteria applied: PS3,PS4,PM5 Clinical Features: Focal-onset seizure (present) , Atypical behavior (present) , Status epilepticus (present) , Abnormal temper tantrums (present) Sex: female
Pathogenic (Dec 12, 2017)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Primary familial hypertrophic cardiomyopathy Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000917820.1 First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019	Publications: PubMed (7) PubMed: 25031304‚ 15166115‚ 16858239‚ 15114369‚ 15563892‚ 9562578‚ 9742053 Comment: Variant summary: The MYBPC3 c.772G>A (p.Glu258Lys) variant involves the alteration of a conserved nucleotide located just one nucleotide upstream from an exon-intron junction. 3/5 in … (more) Variant summary: The MYBPC3 c.772G>A (p.Glu258Lys) variant involves the alteration of a conserved nucleotide located just one nucleotide upstream from an exon-intron junction. 3/5 in silico tools predict a damaging outcome for this variant. 5/5 programs via Alamut predict that this variant affects normal splicing. Multiple functional studies confirmed that the variant leads to exon 6 skipping resulting in a premature stop codon (Anderson_2004, Helms_2014). Heterozygous loss-of-function due to mutations in the MYBPC3 gene is an established disease mechanism in HCM. This variant was found in 5/270526 control chromosomes at a frequency of 0.0000185, which does not exceed the estimated maximal expected allele frequency of a pathogenic MYBPC3 variant (0.0010005). The variant has been recurrently found in numerous patients with HCM and is reported to cosegregate with the disease (Niimura_1998; Girolami_2006). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
Pathogenic (Mar 21, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hypertrophic cardiomyopathy Affected status: yes Allele origin: germline	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute Accession: SCV000996340.2 First in ClinVar: Nov 02, 2019 Last updated: Jan 09, 2020	Publications: PubMed (31) PubMed: 15114369‚ 16858239‚ 17908752‚ 12951062‚ 9562578‚ 15563892‚ 20173211‚ 18374358‚ 20359594‚ 19808356‚ 15519027‚ 12707239‚ 12974739‚ 20031602‚ 18533079‚ 20159828‚ 18957093‚ 19574547‚ 15769446‚ 22563033‚ 20414521‚ 22907696‚ 23527136‚ 23690394‚ 23980194‚ 23782526‚ 24865491‚ 25031304‚ 19590044‚ 22267749‚ 23233322 Comment: The MYBPC3 Glu258Lys is a rare variant, with an allele frequency of 0.000039 in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). This variant has been reported … (more) The MYBPC3 Glu258Lys is a rare variant, with an allele frequency of 0.000039 in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). This variant has been reported in multiple unrelated HCM patients (see references), and is observed to be shared in up to ~14% of unrelated HCM cases in Italian cohorts, suggesting a founder effect (Girolami et al, 2006; Olivotto et al, 2008). Segregation analyses support its pathogenic role (Niimura et al., 1998; Girolami et al., 2006). In silico tools (SIFT, PolyPhen-2, MutationTaster) predict this variant to be disease causing. Furthermore, this variant affects the splice site consensus sequence (last base of exon 6) and has been shown to result in truncated MYBPC3 protein due to exon skipping (Anderson et al., 2004; Sarikas et al., 2005; Helms AS, et al., 2014). Functional studies have shown that the truncated protein is incorporated into cardiac sarcomeres and impairs contractile function (De Lange et al., 2013). We have identified MYBPC3 Glu258Lys in 3 HCM probands. In summary, based on rarity in the general population, observation in multiple unrelated HCM cases and because loss of function is a mechanism of disease for MYBPC3, we classify this variant as "pathogenic". (less)
Pathogenic (May 02, 2023)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	Hypertrophic cardiomyopathy 4 Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV004014736.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023	Publications: PubMed (6) PubMed: 27532257‚ 19574547‚ 19590044‚ 23980194‚ 18533079‚ 15114369 Comment: The MYBPC3 c.772G>A (p.Glu258Lys) missense variant results in the substitution of glutamic acid at amino acid position 258 with lysine. Across a selection of the … (more) The MYBPC3 c.772G>A (p.Glu258Lys) missense variant results in the substitution of glutamic acid at amino acid position 258 with lysine. Across a selection of the available literature, this variant has been identified in a heterozygous state in greater than 50 unrelated individuals with hypertrophic cardiomyopathy (PMID: 18533079; PMID: 27532257). The highest frequency of this allele in the Genome Aggregation Database is 0.00004410 in the European (non-Finnish) population (version 3.1.2). This variant's nucleotide position coincides with a canonical splice donor site. Functional experiments using patient tissues have demonstrated an effect on splicing that leads to skipping of exon 6, which results in nonsense-mediated mRNA decay due to a premature stop codon (PMID: 15114369; PMID: 19574547). In addition, transgenic rescue experiments performed in cultured murine cardiomyocytes have demonstrated reduced contractile force and altered contractile kinetics due to the presence of the p.Glu258Lys variant independent of any effects on splicing (PMID: 23980194). A knock-in mouse carrying this variant has been developed and displays the hallmark phenotype of hypertrophic cardiomyopathy (PMID: 19590044). Based on the available evidence, the c.772G>A (p.Glu258Lys) variant is classified as pathogenic for hypertrophic cardiomyopathy. (less)
Pathogenic (Apr 06, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001359738.3 First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024	Publications: PubMed (18) PubMed: 1853307‚ 9562578‚ 12707239‚ 12951062‚ 12974739‚ 14563344‚ 15114369‚ 15563892‚ 16858239‚ 18533079‚ 19574547‚ 19590044‚ 19808356‚ 22267749‚ 23233322‚ 23980194‚ 25031304‚ 30645170 Comment: This variant alters the conserved c.G nucleotide at the last nucleotide position of exon 6 of the MYBPC3 gene. RNA studies using blood and myocardial … (more) This variant alters the conserved c.G nucleotide at the last nucleotide position of exon 6 of the MYBPC3 gene. RNA studies using blood and myocardial samples from carriers have shown that this variant causes out-of-frame skipping of exon 6, resulting in premature truncation (PMID: 15114369, 19574547, 25031304, 30645170). A study using engineered mouse cardiac tissue has shown that this variant disrupts the interaction between MYBPC3 and myosin protein and accelerates contractile kinetics (PMID: 23980194). In a knock-in mouse model, this variant causes left ventricular hypertrophy and reduced fractional shortening, consistent with hypertrophic cardiomyopathy phenotype (PMID: 19590044). This variant has been reported in over 50 individuals affected with hypertrophic cardiomyopathy from various populations (PMID: 12707239, 12951062, 14563344, 12974739, 15114369, 15563892, 16858239, 1853307, 19808356, 19574547, 22267749, 23233322, 30645170, Marschall et al., 2019) and is particularly common in the Italian population (PMID: 16858239, 18533079). This variant has been shown to segregate with disease in a family study (PMID: 9562578). This variant has been identified in 6/272910 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. (less)
Pathogenic (Feb 26, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy Affected status: yes Allele origin: somatic	Loeys Lab, Universiteit Antwerpen Accession: SCV001572568.1 First in ClinVar: Apr 30, 2021 Last updated: Apr 30, 2021	Publications: PubMed (9) PubMed: 9562578‚ 12951062‚ 15519027‚ 15769446‚ 25031304‚ 12707239‚ 23980194‚ 19590044‚ 18533079 Comment: This sequence change results in a missense variant in the MYBPC3 gene (p.(Glu258Lys)). This variant is present in population databases (GnomAD 6/272910). This variant has … (more) This sequence change results in a missense variant in the MYBPC3 gene (p.(Glu258Lys)). This variant is present in population databases (GnomAD 6/272910). This variant has been reported in the literature in several unrelated individuals/families with HCM and cosegregated with disease (PP1) (PMID: 9562578; PMID: 12951062; PMID: 15519027; PMID: 12707239; PMID: 16858239). It was identified as a common variant among HCM patients in Italy (21% of the cases studied) (PMID: 18533079) (PS4). The variant affects a highly conserved position and alters the last base of exon 6, leading to skipping of exon 6. In cardiac tissue of HCM patients carrying the variant, no missense transcript was detected, indicating that the variant resulted in truncating mutant transcripts. These transcript however, did not result in any detectable truncated protein, since only wild-type protein was detected (PMID: 25031304). In neonatal rat cardiomyocytes it was shown that the truncated transcript underwent degradation by the ubiquitin-proteasome system ( PMID: 15769446) (PVS1). In murine a-engineered cardiac tissue the variant resulted in accelerated contractile kinetics, disruption of twitch force and absence of the interaction between cMyBP-C and myosin heavy chain sub-fragment 2 (PMID: 23980194) (PS3). In a knock-in mouse model homozygous mice showed left ventricular hypertrophy, reduced fractional shortening, and interstitial fibrosis; heterozygotes had no major phenotype.(PMID: 19590044). We identified this variant in a female HCM patient who carried an additional MYBPC3 variant (c.1828G>A, classified as variant of unknown significance). In conclusion this variant was classified as a pathogenic variant according to ACMG-guidelines (PVS1; PP1; PS4;PS3). (less) Number of individuals with the variant: 1 Indication for testing: Cardiomyopathy, hypertrophic, 1 Family history: no Sex: female Tissue: blood Secondary finding: no
Pathogenic (Apr 06, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV002103243.1 First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022	Comment: PS3, PS4, PP1, PP3
Pathogenic (Nov 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004834726.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (18) PubMed: 1853307‚ 9562578‚ 12707239‚ 12951062‚ 12974739‚ 14563344‚ 15114369‚ 15563892‚ 16858239‚ 18533079‚ 19574547‚ 19590044‚ 19808356‚ 22267749‚ 23233322‚ 23980194‚ 25031304‚ 30645170 Comment: This variant alters the conserved c.G nucleotide at the last nucleotide position of exon 6 of the MYBPC3 gene. RNA studies using blood and myocardial … (more) This variant alters the conserved c.G nucleotide at the last nucleotide position of exon 6 of the MYBPC3 gene. RNA studies using blood and myocardial samples from carriers have shown that this variant causes out-of-frame skipping of exon 6, resulting in premature truncation (PMID: 15114369, 19574547, 25031304, 30645170). A study using engineered mouse cardiac tissue has shown that this variant disrupts the interaction between MYBPC3 and myosin protein and accelerates contractile kinetics (PMID: 23980194). In a knock-in mouse model, this variant causes left ventricular hypertrophy and reduced fractional shortening, consistent with hypertrophic cardiomyopathy phenotype (PMID: 19590044). This variant has been reported in over 50 individuals affected with hypertrophic cardiomyopathy from various populations (PMID: 12707239, 12951062, 14563344, 12974739, 15114369, 15563892, 16858239, 1853307, 19808356, 19574547, 22267749, 23233322, 30645170, Marschall et al., 2019) and is particularly common in the Italian population (PMID: 16858239, 18533079). This variant has been shown to segregate with disease in a family study (PMID: 9562578). This variant has been identified in 6/272910 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. (less) Number of individuals with the variant: 4
Pathogenic (Sep 21, 2015)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Hypertrophic cardiomyopathy 4 Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Study: VKGL Data-share Consensus Accession: SCV000744867.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018
Pathogenic (Aug 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001961282.20 First in ClinVar: Oct 08, 2021 Last updated: Oct 20, 2024	Comment: MYBPC3: PP1:Strong, PM5, PS3:Moderate, PS4:Moderate, PM2:Supporting, BP4 Number of individuals with the variant: 2
Pathogenic (Feb 26, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy 4 Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001367566.2 First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,Ps4-MOD,PM2,PP1-M,PP3.
Pathogenic (Jun 14, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004175449.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023	Publications: PubMed (8) PubMed: 3980194‚ 9562578‚ 16858239‚ 19590044‚ 25031304‚ 28679633‚ 30645170‚ 34097875 Comment: The MYBPC3 c.772G>A variant is classified as Pathogenic (PS3, PS4) MYBPC3 c.772G>A is a single nucleotide variant located at the last nucleotide of exon 6/35 … (more) The MYBPC3 c.772G>A variant is classified as Pathogenic (PS3, PS4) MYBPC3 c.772G>A is a single nucleotide variant located at the last nucleotide of exon 6/35 of the MYBPC3 gene which is predicted to change the amino acid glutamic acid at position 258 in the protein to lysine. The variant has been reported in excess of 70 probands with a clinical presentation of hypertrophic cardiomyopathy (PS4) and is reported to segregate with disease in multiple families (PMID#9562578, 16858239). Well-established functional studies show this variant impacts splicing, resulting in a deletion of exon 6 and downstream truncation of the MYBPC3 protein (PMID#3980194, 25031304, 28679633, 30645170, 34097875, 19590044) (PS3). This variant has been reported in dbSNP (rs397516074), reported as disease causing in the HGMD database (CM981322) and is reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 42792). (less)
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy 4 Affected status: yes Allele origin: germline	3billion Accession: SCV002058951.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Publications: PMID:25031304 PMID:25031304 Comment: Missense variant: previously reported to alter splicing and result in a loss of normal protein fucnction through nonsense-mediated decay (NMD) or protein truncation (PMID: 25031304, … (more) Missense variant: previously reported to alter splicing and result in a loss of normal protein fucnction through nonsense-mediated decay (NMD) or protein truncation (PMID: 25031304, PVS!_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000022, PM2_M). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000042792). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Left ventricular hypertrophy (present)
Pathogenic (Sep 21, 2022)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10 Affected status: yes Allele origin: germline	New York Genome Center Accession: SCV003925302.1 First in ClinVar: May 20, 2023 Last updated: May 20, 2023	Comment: The c.772G>A variant in MYBPC3 has previously been reported in individuals with noncompaction cardiomyopathy [PMID:29447731], hypertrophic cardiomyopathy [PMID:15114369,25031304, 22267749, 23233322, 30645170, 30972196], and was found … (more) The c.772G>A variant in MYBPC3 has previously been reported in individuals with noncompaction cardiomyopathy [PMID:29447731], hypertrophic cardiomyopathy [PMID:15114369,25031304, 22267749, 23233322, 30645170, 30972196], and was found to segregate in many additional affected family members [PMID:9562578]. This variant has been deposited in ClinVar [ClinVar ID: 42792] as Pathogenic/Likely Pathogenic. The c.772G>A variant is observed in 17 alleles (0.0021% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.772G>A variant in MYBPC3 is located in exon 6 of this 35-exon gene and is predicted to replace a moderately conserved glutamic acid with lysine amino acid at position 285 p.(Arg123Gln) in the phosphorylation domain of the c1 motif of the encoded protein [PMID:28658286,23233322, 15114369]. In addition, the c.772G>A variant is located one nucleotide away from the exon-intron junction of exon 6, therefore it may also affect the splicing. In vitro functional RNA studies using blood and myocardial samples have shown to cause out-of-frame skipping of exon 6, resulting in premature truncation cells carrying c.772G>A variant [PMID: 15114369, 25031304, 30645170]. Besides, this variant has demonstrated to alter protein interactions, contractile kinetics and caused left ventricular hypertrophy, reduced fractional shortening consistent with hypertrophic cardiomyopathy phenotype in mouse models [PMID: 19590044]. In silico predictions are inconclusive for p.(Arg123Gln) variant's effect [(CADD v1.6 = 51, REVEL = 0.616)]. Based on available evidence, this c.772G>A p.(Glu258Lys) variant identified in MYBPC3 is classified as Pathogenic. (less) Clinical Features: Cardiomyopathy (present) Secondary finding: no
Pathogenic (May 30, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV001332760.4 First in ClinVar: May 31, 2020 Last updated: Feb 04, 2024
Pathogenic (Jul 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005199347.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Hypertrophic cardiomyopathy 4 Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000733061.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Pathogenic (Oct 28, 2015)	no assertion criteria provided Method: provider interpretation	not provided Affected status: unknown Allele origin: germline	Stanford Center for Inherited Cardiovascular Disease, Stanford University Accession: SCV000924856.1 First in ClinVar: Jun 29, 2019 Last updated: Jun 29, 2019
Pathogenic (Nov 02, 2021)	no assertion criteria provided Method: clinical testing	Left ventricular noncompaction 10 Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein Accession: SCV002583319.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Uncertain significance (-)	no assertion criteria provided Method: research	hypertrophic cardiomyopathy Affected status: yes Allele origin: unknown	Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics Accession: SCV005374520.1 First in ClinVar: Oct 20, 2024 Last updated: Oct 20, 2024
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001954161.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
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Comment:

The p.Glu258Lys variant in MYBPC3 has been reported in multiple HCM probands and segregated in many additional affected family members (Girolami 2006, Marston 2009, Niimura 1998, Nanni 2003, Olivotto 2008, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 42792) and has been identified in 4/124374 of European and in 2/23498 of African chromosomes by gnomAD (https://gnomad.broadinstitute.org/). The p.Glu258Lys variant is located in the last base of exon 6, which is part of the 5â€™ splice region. Functional studies using patient RNA have shown that this alteration affects splicing, leading to skipping of exon 6, which is predicted to result in a frameshift, premature termination and therefore likely in a loss of function (Andersen 2004, Martson 2009). Heterozygous loss of function of the MYBPC3 gene is an established disease mechanism in autosomal dominant HCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM based on case observations, segregation with disease, low frequency in the general population and observed impact on splicing. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2_Supporting, PS3_Moderate.

Comment:

The c.772G>A pathogenic mutation (also known as p.E258K), located in coding exon 6 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 772. The glutamic acid at codon 258 is replaced by lysine, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 6, which makes it likely to have some effect on normal mRNA splicing. In one study, RT-qPCR analysis showed that the altered allele resulted in skipping of exon 6 and all of the mutant transcripts were truncated (Helms AS et al. Circ Cardiovasc Genet. 2014;7(4):434-43). This alteration has been identified in multiple individuals with hypertrophic cardiomyopathy (HCM) with co-segregation and a suggested founder effect (Niimura H et al. N Engl J Med. 1998;338(18):1248-57; Girolami F et al. J Cardiovasc Med (Hagerstown). 2006;7(8):601-7; Bongini C. Am J Cardiol. 2016;117(7):1151-9). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Comment:

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 258 of the MYBPC3 protein (p.Glu258Lys). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs397516074, gnomAD 0.009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 9562578, 12707239, 15563892, 18533079, 20031602, 22267749, 23233322). This variant is also known as E264K. ClinVar contains an entry for this variant (Variation ID: 42792). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MYBPC3 function (PMID: 15769446, 19590044, 23980194). Studies have shown that this missense change results in skipping of exon 6 and introduces a premature termination codon (PMID: 15114369, 19574547, 25031304). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

Comment:

Reported to segregate with disease in multiple families (Niimura et al., 1998; Richard et al., 2003; Ho et al., 2009; Zhao et al., 2017); Proposed as an Italian founder mutation (Girolami et al., 2006; Olivotto et al., 2008); Observed in 6/272910 global alleles in large population cohorts (Lek et al., 2016); Located in the last nucleotide position of exon 6, which is part of the splice donor site; Functional studies have demonstrated that the E258K variant leads to aberrant gene splicing of exon 6 (Andersen et al., 2004; Vignier et al., 2009; Helms et al., 2014); Additional studies suggest this variant may result in rapid protein degradation (Sarikas et al., 2005; Vignier et al., 2009) or, if abnormal protein is expressed, it may lead to altered protein interaction and contractile kinetics (De Lange et al., 2013); In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID 42792; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26671970, 30550750, 27532257, 23233322, 15114369, 29875424, 30165862, 28687478, 28679633, 30972196, 9562578, 19574547, 20359594, 18533079, 23283745, 22907696, 25031304, 23980194, 12951062, 26914223, 25971843, 21310275, 12707239, 15563892, 15519027, 23527136, 19590044, 15769446, 20031602, 22267749, 16858239, 28450932, 28790153, 29524613, 28916354, 12974739, 18957093, 27574918, 27267291, 27600940, 26869393, 25351510, 29447731, 30645170, 30446606, 31006259, 31737537, 31447099, 33673806, 33297573, 32686758)

Comment:

The c.772G>A (p.Glu258Lys) variant in the MYBPC3 gene has been reported in multiple unrelated individuals with hypertrophic cardiomyopathies (PMID: 9562578, 12707239, 15114369, 15563892, 16858239, 18533079, 23233322, 25031304). This variant has an extremely low frequency in large databases of genetic variation in the general population. mRNA studies demonstrated that this variant resulted in skipping of exon 6 (PMID: 15114369, 25031304). Therefore, this c.772G>A (p.Glu258Lys) variant in the MYBPC3 gene is classified as pathogenic.

Comment:

Variant summary: The MYBPC3 c.772G>A (p.Glu258Lys) variant involves the alteration of a conserved nucleotide located just one nucleotide upstream from an exon-intron junction. 3/5 in silico tools predict a damaging outcome for this variant. 5/5 programs via Alamut predict that this variant affects normal splicing. Multiple functional studies confirmed that the variant leads to exon 6 skipping resulting in a premature stop codon (Anderson_2004, Helms_2014). Heterozygous loss-of-function due to mutations in the MYBPC3 gene is an established disease mechanism in HCM. This variant was found in 5/270526 control chromosomes at a frequency of 0.0000185, which does not exceed the estimated maximal expected allele frequency of a pathogenic MYBPC3 variant (0.0010005). The variant has been recurrently found in numerous patients with HCM and is reported to cosegregate with the disease (Niimura_1998; Girolami_2006). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

Comment:

The MYBPC3 Glu258Lys is a rare variant, with an allele frequency of 0.000039 in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). This variant has been reported in multiple unrelated HCM patients (see references), and is observed to be shared in up to ~14% of unrelated HCM cases in Italian cohorts, suggesting a founder effect (Girolami et al, 2006; Olivotto et al, 2008). Segregation analyses support its pathogenic role (Niimura et al., 1998; Girolami et al., 2006). In silico tools (SIFT, PolyPhen-2, MutationTaster) predict this variant to be disease causing. Furthermore, this variant affects the splice site consensus sequence (last base of exon 6) and has been shown to result in truncated MYBPC3 protein due to exon skipping (Anderson et al., 2004; Sarikas et al., 2005; Helms AS, et al., 2014). Functional studies have shown that the truncated protein is incorporated into cardiac sarcomeres and impairs contractile function (De Lange et al., 2013). We have identified MYBPC3 Glu258Lys in 3 HCM probands. In summary, based on rarity in the general population, observation in multiple unrelated HCM cases and because loss of function is a mechanism of disease for MYBPC3, we classify this variant as "pathogenic".

Comment:

The MYBPC3 c.772G>A (p.Glu258Lys) missense variant results in the substitution of glutamic acid at amino acid position 258 with lysine. Across a selection of the available literature, this variant has been identified in a heterozygous state in greater than 50 unrelated individuals with hypertrophic cardiomyopathy (PMID: 18533079; PMID: 27532257). The highest frequency of this allele in the Genome Aggregation Database is 0.00004410 in the European (non-Finnish) population (version 3.1.2). This variant's nucleotide position coincides with a canonical splice donor site. Functional experiments using patient tissues have demonstrated an effect on splicing that leads to skipping of exon 6, which results in nonsense-mediated mRNA decay due to a premature stop codon (PMID: 15114369; PMID: 19574547). In addition, transgenic rescue experiments performed in cultured murine cardiomyocytes have demonstrated reduced contractile force and altered contractile kinetics due to the presence of the p.Glu258Lys variant independent of any effects on splicing (PMID: 23980194). A knock-in mouse carrying this variant has been developed and displays the hallmark phenotype of hypertrophic cardiomyopathy (PMID: 19590044). Based on the available evidence, the c.772G>A (p.Glu258Lys) variant is classified as pathogenic for hypertrophic cardiomyopathy.

Comment:

This variant alters the conserved c.G nucleotide at the last nucleotide position of exon 6 of the MYBPC3 gene. RNA studies using blood and myocardial samples from carriers have shown that this variant causes out-of-frame skipping of exon 6, resulting in premature truncation (PMID: 15114369, 19574547, 25031304, 30645170). A study using engineered mouse cardiac tissue has shown that this variant disrupts the interaction between MYBPC3 and myosin protein and accelerates contractile kinetics (PMID: 23980194). In a knock-in mouse model, this variant causes left ventricular hypertrophy and reduced fractional shortening, consistent with hypertrophic cardiomyopathy phenotype (PMID: 19590044). This variant has been reported in over 50 individuals affected with hypertrophic cardiomyopathy from various populations (PMID: 12707239, 12951062, 14563344, 12974739, 15114369, 15563892, 16858239, 1853307, 19808356, 19574547, 22267749, 23233322, 30645170, Marschall et al., 2019) and is particularly common in the Italian population (PMID: 16858239, 18533079). This variant has been shown to segregate with disease in a family study (PMID: 9562578). This variant has been identified in 6/272910 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.

Comment:

This sequence change results in a missense variant in the MYBPC3 gene (p.(Glu258Lys)). This variant is present in population databases (GnomAD 6/272910). This variant has been reported in the literature in several unrelated individuals/families with HCM and cosegregated with disease (PP1) (PMID: 9562578; PMID: 12951062; PMID: 15519027; PMID: 12707239; PMID: 16858239). It was identified as a common variant among HCM patients in Italy (21% of the cases studied) (PMID: 18533079) (PS4). The variant affects a highly conserved position and alters the last base of exon 6, leading to skipping of exon 6. In cardiac tissue of HCM patients carrying the variant, no missense transcript was detected, indicating that the variant resulted in truncating mutant transcripts. These transcript however, did not result in any detectable truncated protein, since only wild-type protein was detected (PMID: 25031304). In neonatal rat cardiomyocytes it was shown that the truncated transcript underwent degradation by the ubiquitin-proteasome system ( PMID: 15769446) (PVS1). In murine a-engineered cardiac tissue the variant resulted in accelerated contractile kinetics, disruption of twitch force and absence of the interaction between cMyBP-C and myosin heavy chain sub-fragment 2 (PMID: 23980194) (PS3). In a knock-in mouse model homozygous mice showed left ventricular hypertrophy, reduced fractional shortening, and interstitial fibrosis; heterozygotes had no major phenotype.(PMID: 19590044). We identified this variant in a female HCM patient who carried an additional MYBPC3 variant (c.1828G>A, classified as variant of unknown significance). In conclusion this variant was classified as a pathogenic variant according to ACMG-guidelines (PVS1; PP1; PS4;PS3).

Comment:

The MYBPC3 c.772G>A variant is classified as Pathogenic (PS3, PS4) MYBPC3 c.772G>A is a single nucleotide variant located at the last nucleotide of exon 6/35 of the MYBPC3 gene which is predicted to change the amino acid glutamic acid at position 258 in the protein to lysine. The variant has been reported in excess of 70 probands with a clinical presentation of hypertrophic cardiomyopathy (PS4) and is reported to segregate with disease in multiple families (PMID#9562578, 16858239). Well-established functional studies show this variant impacts splicing, resulting in a deletion of exon 6 and downstream truncation of the MYBPC3 protein (PMID#3980194, 25031304, 28679633, 30645170, 34097875, 19590044) (PS3). This variant has been reported in dbSNP (rs397516074), reported as disease causing in the HGMD database (CM981322) and is reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 42792).

Comment:

Missense variant: previously reported to alter splicing and result in a loss of normal protein fucnction through nonsense-mediated decay (NMD) or protein truncation (PMID: 25031304, PVS!_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000022, PM2_M). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000042792). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

The c.772G>A variant in MYBPC3 has previously been reported in individuals with noncompaction cardiomyopathy [PMID:29447731], hypertrophic cardiomyopathy [PMID:15114369,25031304, 22267749, 23233322, 30645170, 30972196], and was found to segregate in many additional affected family members [PMID:9562578]. This variant has been deposited in ClinVar [ClinVar ID: 42792] as Pathogenic/Likely Pathogenic. The c.772G>A variant is observed in 17 alleles (0.0021% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.772G>A variant in MYBPC3 is located in exon 6 of this 35-exon gene and is predicted to replace a moderately conserved glutamic acid with lysine amino acid at position 285 p.(Arg123Gln) in the phosphorylation domain of the c1 motif of the encoded protein [PMID:28658286,23233322, 15114369]. In addition, the c.772G>A variant is located one nucleotide away from the exon-intron junction of exon 6, therefore it may also affect the splicing. In vitro functional RNA studies using blood and myocardial samples have shown to cause out-of-frame skipping of exon 6, resulting in premature truncation cells carrying c.772G>A variant [PMID: 15114369, 25031304, 30645170]. Besides, this variant has demonstrated to alter protein interactions, contractile kinetics and caused left ventricular hypertrophy, reduced fractional shortening consistent with hypertrophic cardiomyopathy phenotype in mouse models [PMID: 19590044]. In silico predictions are inconclusive for p.(Arg123Gln) variant's effect [(CADD v1.6 = 51, REVEL = 0.616)]. Based on available evidence, this c.772G>A p.(Glu258Lys) variant identified in MYBPC3 is classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Protein haploinsufficiency drivers identify MYBPC3 variants that cause hypertrophic cardiomyopathy.	Suay-Corredera C	The Journal of biological chemistry	2021	PMID: 34097875
Key Value of RNA Analysis of MYBPC3 Splice-Site Variants in Hypertrophic Cardiomyopathy.	Singer ES	Circulation. Genomic and precision medicine	2019	PMID: 30645170
Identification of pathogenic gene mutations in LMNA and MYBPC3 that alter RNA splicing.	Ito K	Proceedings of the National Academy of Sciences of the United States of America	2017	PMID: 28679633
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.	Walsh R	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 27532257
An Investigation of the Molecular Mechanism of Double cMyBP-C Mutation in a Patient with End-Stage Hypertrophic Cardiomyopathy.	Gajendrarao P	Journal of cardiovascular translational research	2015	PMID: 25971843
Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity.	Alfares AA	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25611685
Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy.	Lopes LR	Heart (British Cardiac Society)	2015	PMID: 25351510
Sarcomere mutation-specific expression patterns in human hypertrophic cardiomyopathy.	Helms AS	Circulation. Cardiovascular genetics	2014	PMID: 25031304
Rare variants in genes encoding MuRF1 and MuRF2 are modifiers of hypertrophic cardiomyopathy.	Su M	International journal of molecular sciences	2014	PMID: 24865491
Characterization of a phenotype-based genetic test prediction score for unrelated patients with hypertrophic cardiomyopathy.	Bos JM	Mayo Clinic proceedings	2014	PMID: 24793961
Distinguishing hypertrophic cardiomyopathy-associated mutations from background genetic noise.	Kapplinger JD	Journal of cardiovascular translational research	2014	PMID: 24510615
A systematic approach to assessing the clinical significance of genetic variants.	Duzkale H	Clinical genetics	2013	PMID: 24033266
E258K HCM-causing mutation in cardiac MyBP-C reduces contractile force and accelerates twitch kinetics by disrupting the cMyBP-C and myosin S2 interaction.	De Lange WJ	The Journal of general physiology	2013	PMID: 23980194
Somatic MYH7, MYBPC3, TPM1, TNNT2 and TNNI3 mutations in sporadic hypertrophic cardiomyopathy.	Núñez L	Circulation journal : official journal of the Japanese Circulation Society	2013	PMID: 23782526
Comparison of echocardiographic and cardiac magnetic resonance imaging in hypertrophic cardiomyopathy sarcomere mutation carriers without left ventricular hypertrophy.	Valente AM	Circulation. Cardiovascular genetics	2013	PMID: 23690394
Molecular modeling of disease causing mutations in domain C1 of cMyBP-C.	Gajendrarao P	PloS one	2013	PMID: 23527136
Multiple gene mutations, not the type of mutation, are the modifier of left ventricle hypertrophy in patients with hypertrophic cardiomyopathy.	Zou Y	Molecular biology reports	2013	PMID: 23283745
Early results of sarcomeric gene screening from the Egyptian National BA-HCM Program.	Kassem HSh	Journal of cardiovascular translational research	2013	PMID: 23233322
Uptake of cardiac screening and genetic testing among hypertrophic and dilated cardiomyopathy families.	Miller EM	Journal of genetic counseling	2013	PMID: 23054336
A case of compound mutations in the MYBPC3 gene associated with biventricular hypertrophy and neonatal death.	Marziliano N	Neonatology	2012	PMID: 22907696
Prevalence and clinical profile of myocardial crypts in hypertrophic cardiomyopathy.	Maron MS	Circulation. Cardiovascular imaging	2012	PMID: 22563033
Cardiac myosin binding protein-C mutations in families with hypertrophic cardiomyopathy: disease expression in relation to age, gender, and long term outcome.	Page SP	Circulation. Cardiovascular genetics	2012	PMID: 22267749
Microvascular function is selectively impaired in patients with hypertrophic cardiomyopathy and sarcomere myofilament gene mutations.	Olivotto I	Journal of the American College of Cardiology	2011	PMID: 21835320
[Study of mutations causing hypertrophic cardiomyopathy in a group of patients from Espirito Santo, Brazil].	Marsiglia JD	Arquivos brasileiros de cardiologia	2010	PMID: 20414521
Clinical features and outcome of hypertrophic cardiomyopathy associated with triple sarcomere protein gene mutations.	Girolami F	Journal of the American College of Cardiology	2010	PMID: 20359594
Efficacy of catheter ablation for atrial fibrillation in hypertrophic cardiomyopathy: impact of age, atrial remodelling, and disease progression.	Di Donna P	Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology	2010	PMID: 20173211
Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies.	Predmore JM	Circulation	2010	PMID: 20159828
Echocardiographic strain imaging to assess early and late consequences of sarcomere mutations in hypertrophic cardiomyopathy.	Ho CY	Circulation. Cardiovascular genetics	2009	PMID: 20031602
Expression patterns of cardiac myofilament proteins: genomic and protein analysis of surgical myectomy tissue from patients with obstructive hypertrophic cardiomyopathy.	Theis JL	Circulation. Heart failure	2009	PMID: 19808356
Nonsense-mediated mRNA decay and ubiquitin-proteasome system regulate cardiac myosin-binding protein C mutant levels in cardiomyopathic mice.	Vignier N	Circulation research	2009	PMID: 19590044
Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency.	Marston S	Circulation research	2009	PMID: 19574547
Adverse events in families with hypertrophic or dilated cardiomyopathy and mutations in the MYBPC3 gene.	Ehlermann P	BMC medical genetics	2008	PMID: 18957093
Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy.	Olivotto I	Mayo Clinic proceedings	2008	PMID: 18533079
ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007.	Richards CS	Genetics in medicine : official journal of the American College of Medical Genetics	2008	PMID: 18414213
Shared genetic causes of cardiac hypertrophy in children and adults.	Morita H	The New England journal of medicine	2008	PMID: 18403758
Crystal structure of the C1 domain of cardiac myosin binding protein-C: implications for hypertrophic cardiomyopathy.	Govada L	Journal of molecular biology	2008	PMID: 18374358
Contribution of inherited heart disease to sudden cardiac death in childhood.	Hofman N	Pediatrics	2007	PMID: 17908752
A molecular screening strategy based on beta-myosin heavy chain, cardiac myosin binding protein C and troponin T genes in Italian patients with hypertrophic cardiomyopathy.	Girolami F	Journal of cardiovascular medicine (Hagerstown, Md.)	2006	PMID: 16858239
Impairment of the ubiquitin-proteasome system by truncated cardiac myosin binding protein C mutants.	Sarikas A	Cardiovascular research	2005	PMID: 15769446
Mutations profile in Chinese patients with hypertrophic cardiomyopathy.	Song L	Clinica chimica acta; international journal of clinical chemistry	2005	PMID: 15563892
Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy.	Van Driest SL	Journal of the American College of Cardiology	2004	PMID: 15519027
Cardiac myosin binding protein C: its role in physiology and disease.	Flashman E	Circulation research	2004	PMID: 15166115
Genetic and phenotypic characterization of mutations in myosin-binding protein C (MYBPC3) in 81 families with familial hypertrophic cardiomyopathy: total or partial haploinsufficiency.	Andersen PS	European journal of human genetics : EJHG	2004	PMID: 15114369
The 2373insG mutation in the MYBPC3 gene is a founder mutation, which accounts for nearly one-fourth of the HCM cases in the Netherlands.	Alders M	European heart journal	2003	PMID: 14563344
Mutation spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy.	Erdmann J	Clinical genetics	2003	PMID: 12974739
Hypertrophic cardiomyopathy: two homozygous cases with "typical" hypertrophic cardiomyopathy and three new mutations in cases with progression to dilated cardiomyopathy.	Nanni L	Biochemical and biophysical research communications	2003	PMID: 12951062
Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy.	Richard P	Circulation	2003	PMID: 12707239
Familial hypertrophic cardiomyopathy: from mutations to functional defects.	Bonne G	Circulation research	1998	PMID: 9742053
Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy.	Niimura H	The New England journal of medicine	1998	PMID: 9562578
Circadian variations of platelet aggregability and fibrinolytic activity in healthy subjects.	Jovicić A	Thrombosis research	1991	PMID: 1853307
Botulism intoxication after surgery in the gut.	Isacsohn M	Israel journal of medical sciences	1985	PMID: 3980194
-	-	-	-	PMID: 397516074
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MYBPC3	-	-	-	-
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Text-mined citations for rs397516074 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000256.3(MYBPC3):c.772G>A (p.Glu258Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397516074 ...