VCV000042978.21 - ClinVar

NM_000257.4(MYH7):c.3856G>A (p.Glu1286Lys)

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.

(7)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000257.4(MYH7):c.3856G>A (p.Glu1286Lys)

Variation ID: 42978 Accession: VCV000042978.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q11.2 14: 23419293 (GRCh38) [ NCBI UCSC ] 14: 23888502 (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	May 29, 2016	May 1, 2024	Feb 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000257.4:c.3856G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000248.2:p.Glu1286Lys	missense
NC_000014.9:g.23419293C>T
NC_000014.8:g.23888502C>T
NG_007884.1:g.21369G>A
LRG_384:g.21369G>A
LRG_384t1:c.3856G>A

... more HGVS ... less HGVS

Protein change

E1286K

Other names

Canonical SPDI

NC_000014.9:23419292: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) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

Links

ClinGen: CA014172 dbSNP: rs397516196 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.
MYH7		No evidence available	No evidence available	GRCh38 GRCh37	3643	4925

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.
Hypertrophic cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Jun 17, 2023	RCV000628955.8
Congenital myopathy with fiber type disproportion	Uncertain significance (1)	criteria provided, single submitter	Jan 20, 2020	RCV001198766.2
Cardiomyopathy	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Feb 5, 2024	RCV001525525.6
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Jan 24, 2024	RCV004018776.1
not provided	Uncertain significance (1)	criteria provided, single submitter	Oct 26, 2021	RCV003129764.3
not specified	Uncertain significance (1)	criteria provided, single submitter	Apr 19, 2020	RCV000035871.7

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.
Uncertain significance (Oct 26, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003817677.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (Jan 24, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV005033923.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 22464770‚ 27532257‚ 37904629 Comment: The p.E1286K variant (also known as c.3856G>A), located in coding exon 27 of the MYH7 gene, results from a G to A substitution at nucleotide … (more) The p.E1286K variant (also known as c.3856G>A), located in coding exon 27 of the MYH7 gene, results from a G to A substitution at nucleotide position 3856. The glutamic acid at codon 1286 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in dilated cardiomyopathy (DCM) cohorts; however, clinical details were limited (Walsh R et al. Genet Med, 2017 Feb;19:192-203; Perret C et al. Clin Genet, 2024 Feb;105:185-189). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Apr 19, 2020)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000059522.6 First in ClinVar: May 03, 2013 Last updated: Jul 04, 2020	Publications: PubMed (2) PubMed: 22464770‚ 27532257 Comment: The Glu1286Lys variant in MYH7 has been reported in two young children with dilated cardiomyopathy (DCM), one of whom carried another variant that likely contributed … (more) The Glu1286Lys variant in MYH7 has been reported in two young children with dilated cardiomyopathy (DCM), one of whom carried another variant that likely contributed to disease severity (Lakdawala 2012 PMID:22464770, Walsh 2017 PMID:27532257, LMM data). This variant has also been reported by another clinical laboratory in ClinVar (Variation ID: 42978) and has been identified in 0.003% (3/113766) of European chromosomes in gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting, PM2, PP3. (less) Number of individuals with the variant: 5
Uncertain significance (Jan 20, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myopathy 4A, autosomal dominant Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001369761.2 First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020	Comment: This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in … (more) This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP2,PP3. (less)
Uncertain significance (Mar 09, 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: SCV001735664.3 First in ClinVar: Jun 19, 2021 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 22464770‚ 27532257‚ 31983221 Comment: This missense variant replaces glutamic acid with lysine at codon 1286 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious … (more) This missense variant replaces glutamic acid with lysine at codon 1286 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 22464770, 27532257, 31983221). This variant has been identified in 3/251488 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. (less)
Uncertain significance (Jun 17, 2023)	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: SCV000749863.7 First in ClinVar: May 28, 2018 Last updated: Feb 20, 2024	Publications: PubMed (2) PubMed: 22464770‚ 27532257 Comment: 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 … (more) 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. 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. ClinVar contains an entry for this variant (Variation ID: 42978). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 22464770, 27532257). This variant is present in population databases (rs397516196, gnomAD 0.003%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1286 of the MYH7 protein (p.Glu1286Lys). (less)
Uncertain Significance (Feb 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004820445.1 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 (3) PubMed: 22464770‚ 27532257‚ 31983221 Comment: This missense variant replaces glutamic acid with lysine at codon 1286 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious … (more) This missense variant replaces glutamic acid with lysine at codon 1286 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 22464770, 27532257, 31983221). This variant has been identified in 3/251488 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. (less) Number of individuals with the variant: 5

Comment:

The p.E1286K variant (also known as c.3856G>A), located in coding exon 27 of the MYH7 gene, results from a G to A substitution at nucleotide position 3856. The glutamic acid at codon 1286 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in dilated cardiomyopathy (DCM) cohorts; however, clinical details were limited (Walsh R et al. Genet Med, 2017 Feb;19:192-203; Perret C et al. Clin Genet, 2024 Feb;105:185-189). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.

Comment:

The Glu1286Lys variant in MYH7 has been reported in two young children with dilated cardiomyopathy (DCM), one of whom carried another variant that likely contributed to disease severity (Lakdawala 2012 PMID:22464770, Walsh 2017 PMID:27532257, LMM data). This variant has also been reported by another clinical laboratory in ClinVar (Variation ID: 42978) and has been identified in 0.003% (3/113766) of European chromosomes in gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting, PM2, PP3.

Comment:

This missense variant replaces glutamic acid with lysine at codon 1286 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 22464770, 27532257, 31983221). This variant has been identified in 3/251488 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.

Comment:

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. 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. ClinVar contains an entry for this variant (Variation ID: 42978). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 22464770, 27532257). This variant is present in population databases (rs397516196, gnomAD 0.003%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1286 of the MYH7 protein (p.Glu1286Lys).

Comment:

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
DNA-pools targeted-sequencing as a robust cost-effective method to detect rare variants: Application to dilated cardiomyopathy genetic diagnosis.	Perret C	Clinical genetics	2024	PMID: 37904629
Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy.	Mazzarotto F	Circulation	2020	PMID: 31983221
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
Genetic testing for dilated cardiomyopathy in clinical practice.	Lakdawala NK	Journal of cardiac failure	2012	PMID: 22464770

Text-mined citations for rs397516196 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000257.4(MYH7):c.3856G>A (p.Glu1286Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397516196 ...