NM_000256.3(MYBPC3):c.2320G>A (p.Ala774Thr) AND Hypertrophic cardiomyopathy

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jan 17, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001071057.8

Allele description [Variation Report for NM_000256.3(MYBPC3):c.2320G>A (p.Ala774Thr)]

NM_000256.3(MYBPC3):c.2320G>A (p.Ala774Thr)

Gene:

MYBPC3:myosin binding protein C3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p11.2

Genomic location:

Preferred name:

NM_000256.3(MYBPC3):c.2320G>A (p.Ala774Thr)

HGVS:

NC_000011.10:g.47337783C>T
NG_007667.1:g.19920G>A
NM_000256.3:c.2320G>AMANE SELECT
NP_000247.2:p.Ala774Thr
LRG_386t1:c.2320G>A
LRG_386:g.19920G>A
LRG_386p1:p.Ala774Thr
NC_000011.9:g.47359334C>T
c.2320G>A

Protein change:

A774T

Links:

dbSNP: rs368104687

NCBI 1000 Genomes Browser:

rs368104687

Molecular consequence:

NM_000256.3:c.2320G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hypertrophic cardiomyopathy
Synonyms:: HYPERTROPHIC MYOCARDIOPATHY
Identifiers:: MONDO: MONDO:0005045; MeSH: D002312; MedGen: C0007194; Human Phenotype Ontology: HP:0001639

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000059135	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jun 23, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21839045, 25741868
SCV001236339	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 17, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21839045, 27532257, 33302605, 28492532
SCV004842363	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 13, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 21839045, 27532257, 31983221, 33302605, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000059135

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jun 23, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV001236339

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 17, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004842363

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 13, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	12	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Double or compound sarcomere mutations in hypertrophic cardiomyopathy: a potential link to sudden death in the absence of conventional risk factors.

Maron BJ, Maron MS, Semsarian C.

Heart Rhythm. 2012 Jan;9(1):57-63. doi: 10.1016/j.hrthm.2011.08.009. Epub 2011 Aug 9.

PubMed [citation]

PMID:: 21839045

See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059135.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.Ala774Thr variant in MYBPC3 has been reported in at least 3 individuals with hypertrophic cardiomyopathy and segregated with disease in 2 affected individuals from 1 family (Maron 2012 PMID: 21839045, Walsh 2017 PMID: 27532257, Fernlund 2020 PMID: 33302605 ), as well as in 1 individual with dilated cardiomyopathy (Mazzarotto 2020 PMID: 31983221). It has also been identified in 2/57196 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 42618). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_P, PS4_P, BP4.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001236339.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 774 of the MYBPC3 protein (p.Ala774Thr). This variant is present in population databases (rs368104687, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (PMID: 21839045, 27532257, 33302605). ClinVar contains an entry for this variant (Variation ID: 42618). 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 tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004842363.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	12	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant replaces alanine with threonine at codon 774 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in five individuals affected with hypertrophic cardiomyopathy, including two related individuals who were diagnosed in the neonatal period (PMID: 21839045, 27532257, 33302605). It has also been reported in an individual affected with dilated cardiomyopathy (PMID: 31983221). This variant has been identified in 2/152072 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		12	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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