rs376160714
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP2PP3_Moderate
The ENST00000355349.4(MYH7):c.115G>A(p.Val39Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000607 in 1,614,238 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V39G) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000355349.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.115G>A | p.Val39Met | missense_variant | 3/40 | ENST00000355349.4 | NP_000248.2 | |
MYH7 | NM_001407004.1 | c.115G>A | p.Val39Met | missense_variant | 2/39 | NP_001393933.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.115G>A | p.Val39Met | missense_variant | 3/40 | 1 | NM_000257.4 | ENSP00000347507 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152236Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251460Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135902
GnomAD4 exome AF: 0.0000609 AC: 89AN: 1461884Hom.: 0 Cov.: 35 AF XY: 0.0000674 AC XY: 49AN XY: 727244
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152354Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5AN XY: 74504
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 17, 2021 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 10, 2020 | This variant is associated with the following publications: (PMID: 32833721, 28798025, 18761664, 23299917, 25637381, 27532257, 25569433, 27247418, 12707239) - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 22, 2022 | This missense variant replaces valine with methionine at codon 39 of the MYH7 protein. This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). Computational prediction suggests that this variant may have 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 several individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 18761664, 27247418, 27532257), as well as in an individual affected with Laing distal myopathy (PMID: 32833721). However, some of those individuals also carried a pathogenic variant in the same gene, which suggests that this variant was probably not the primary cause of disease in these individuals. This variant has also been reported in an individual who was not affected with hypertrophic cardiomyopathy (PMID: 30052928). This variant has been identified in 13/282858 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. - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 20, 2024 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 39 of the MYH7 protein (p.Val39Met). This variant is present in population databases (rs376160714, gnomAD 0.05%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy, Laing distal myopathy, and/or left ventricular noncompaction (PMID: 12707239, 27247418, 27532257, 28798025, 32833721). ClinVar contains an entry for this variant (Variation ID: 42827). 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 with a positive predictive value of 95%. 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 familial hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 02, 2020 | The c.115G>A (p.V39M) alteration is located in exon 3 (coding exon 1) of the MYH7 gene. This alteration results from a G to A substitution at nucleotide position 115, causing the valine (V) at amino acid position 39 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 03, 2017 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at