rs121913629
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_000257.4(MYH7):c.2845G>A(p.Glu949Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E949V) has been classified as Uncertain significance.
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.2845G>A | p.Glu949Lys | missense_variant | 23/40 | ENST00000355349.4 | |
MYH7 | NM_001407004.1 | c.2845G>A | p.Glu949Lys | missense_variant | 22/39 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.2845G>A | p.Glu949Lys | missense_variant | 23/40 | 1 | NM_000257.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461892Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 727246
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 28, 2022 | The p.Glu949Lys variant in MYH7 has been reported in >11 individuals with hypertrophic cardiomyopathy (HCM) and as a de novo occurrence in 1 individual with restrictive cardiomyopathy (RCM) and segregated with disease in 1 affected individual from 1 family (Watkins 1992 PMID: 1552912, Kapoor 2017, Zigova 2017 PMID: 28815794, Walsh 2017 PMID: 27532257/LMM data). It was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. Additionally, this variant was classified as Likely Pathogenic on March 22, 2021 by the ClinGen-approved Cardiomyopathy Variant Curation expert panel (Variation ID 14093). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4_Moderate, PM6, PM2_Supporting, PP3. - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen Cardiomyopathy Variant Curation Expert Panel | Mar 22, 2021 | The c.2845G>A (p.Glu949Lys) variant in MYH7 has been reported in 12 individuals with HCM (PS4_Moderate; Watkins 1992 PMID:1552912; Walsh 2017 PMID:27532257; Zigova 2018 PMID:28815794; CHEO pers comm.). This variant segregated with disease in 1 affected relative with HCM (Watkins 1992 PMID:1552912); however, this data is currently insufficient to establish co-segregation with disease and apply PP1. Additionally, this variant has been reported as a de novo occurence in 1 child with RCM (PM6; Kapoor 2017 http://repository.ias.ac.in/114592/1/JPractCardiovascSci33143-8313497_230534.pdf). This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PM6; PM2; PP3 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 11, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 949 of the MYH7 protein (p.Glu949Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 1552912, 27532257, 28815794). ClinVar contains an entry for this variant (Variation ID: 14093). 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. 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. - |
Primary dilated cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 11, 2023 | The c.2845G>A (p.Glu949Lys) variant in MYH7 gene, that encodes for myosin heavy chain 7, has been identified in at least twelve individuals affected with Hypertrophic Cardiomyopathy (HCM) (ClinGen Expert Panel review [ClinVar ID: 14093], PMID:1552912, 27532257, 28815794, 1552912). This variant has been reported as de novo status in a proband with restrictive cardiomyopathy (ClinVar ID: 14093, PMID: NA). In-silico computational prediction tools suggest that this variant may have deleterious effect on the protein function (REVEL score: 0.909). This variant is found to be absent in the general population database (gnomAD) and interpreted as likely pathogenic by the ClinGen Cardiomyopathy Variant Curation Expert Panel (ClinVar ID: 14093). Therefore, the c.2845G>A (p.Glu949Lys) variant in the MYH7 gene is classified as likely pathogenic. - |
Hypertrophic cardiomyopathy 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 23, 1992 | - - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 14, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at