VCV000181178.12 - ClinVar

NM_000257.4(MYH7):c.2229G>C (p.Glu743Asp)

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.

(3)

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.2229G>C (p.Glu743Asp)

Variation ID: 181178 Accession: VCV000181178.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q11.2 14: 23425752 (GRCh38) [ NCBI UCSC ] 14: 23894961 (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	Sep 16, 2024	Jul 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000257.4:c.2229G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000248.2:p.Glu743Asp	missense
NC_000014.9:g.23425752C>G
NC_000014.8:g.23894961C>G
NG_007884.1:g.14910G>C
LRG_384:g.14910G>C
LRG_384t1:c.2229G>C
	P12883:p.Glu743Asp

... more HGVS ... less HGVS

Protein change

E743D

Other names

p.E743D:GAG>GAC

Canonical SPDI

NC_000014.9:23425751:C:G

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.

Links

ClinGen: CA012046 UniProtKB: P12883#VAR_014199 OMIM: 160760.0024 dbSNP: rs397516139 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.
Cardiomyopathy, hypertrophic, midventricular, digenic	Pathogenic (1)	no assertion criteria provided	Nov 30, 2001	RCV000015166.26
not provided	Uncertain significance (1)	criteria provided, single submitter	Jul 23, 2024	RCV000158524.6
Hypertrophic cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Dec 31, 2022	RCV001061140.8

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 (Dec 31, 2022)	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: SCV001225872.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 11733062 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function. ClinVar contains an entry for this variant (Variation ID: 181178). This missense change has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (PMID: 11733062). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 743 of the MYH7 protein (p.Glu743Asp). (less)
Uncertain significance (Jul 23, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000208459.12 First in ClinVar: Feb 24, 2015 Last updated: Sep 16, 2024	Comment: Reported previously in a 13-year-old with early midventricular HCM who also harbored variants in the MYLK2 gene (PMID: 11733062); Not observed at significant frequency in … (more) Reported previously in a 13-year-old with early midventricular HCM who also harbored variants in the MYLK2 gene (PMID: 11733062); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12545186, 18555187, 9243087, 27224906, 30275503, 27532257, 29300372, 11733062) (less)
Pathogenic (Nov 30, 2001)	no assertion criteria provided Method: literature only	CARDIOMYOPATHY, HYPERTROPHIC, MIDVENTRICULAR, DIGENIC Affected status: not provided Allele origin: germline	OMIM Accession: SCV000035423.2 First in ClinVar: Apr 04, 2013 Last updated: Nov 10, 2016	Publications: PubMed (1) PubMed: 11733062 Comment on evidence: Davis et al. (2001) identified a double point mutation in the MYLK2 gene (606566) on the maternal haplotype in a 13-year-old white male proband with … (more) Davis et al. (2001) identified a double point mutation in the MYLK2 gene (606566) on the maternal haplotype in a 13-year-old white male proband with early midventricular hypertrophic cardiomyopathy (see CMH1, 192600). The MYLK2 mutations were ala87 to val (A87V; 606566.0001) and ala95 to glu (A95E; 606566.0002). The proband also inherited a glu743-to-asp mutation (E743D) in the beta-myosin gene (MYH7) from his father. Although the son had significant disease at an early age, the father and mother came to medical attention only after the diagnosis of the son. Echocardiographic evaluation showed that both parents had similarly abnormal asymmetrically thickened hearts. The kindred was too small for linkage analysis, and the authors proposed that the mutant MYLK2 may be functionally abnormal and may consequently stimulate cardiac hypertrophy. Davis et al. (2001) concluded that the increased severity of the disease at such a young age in the proband suggests a compound effect. (less)

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function. ClinVar contains an entry for this variant (Variation ID: 181178). This missense change has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (PMID: 11733062). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 743 of the MYH7 protein (p.Glu743Asp).

Comment:

Reported previously in a 13-year-old with early midventricular HCM who also harbored variants in the MYLK2 gene (PMID: 11733062); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12545186, 18555187, 9243087, 27224906, 30275503, 27532257, 29300372, 11733062)

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
The overall pattern of cardiac contraction depends on a spatial gradient of myosin regulatory light chain phosphorylation.	Davis JS	Cell	2001	PMID: 11733062

Text-mined citations for rs397516139 ...

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.2229G>C (p.Glu743Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397516139 ...