rs121913644
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP2
The NM_000257.4(MYH7):c.2183C>T(p.Ala728Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,613,978 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A728A) has been classified as Likely benign.
Frequency
Consequence
NM_000257.4 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 | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.2183C>T | p.Ala728Val | missense_variant | 20/40 | ENST00000355349.4 | |
MYH7 | NM_001407004.1 | c.2183C>T | p.Ala728Val | missense_variant | 19/39 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.2183C>T | p.Ala728Val | missense_variant | 20/40 | 1 | NM_000257.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000105 AC: 16AN: 152194Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000155 AC: 39AN: 251186Hom.: 0 AF XY: 0.000169 AC XY: 23AN XY: 135752
GnomAD4 exome AF: 0.000138 AC: 202AN: 1461666Hom.: 1 Cov.: 33 AF XY: 0.000136 AC XY: 99AN XY: 727142
GnomAD4 genome ? AF: 0.0000985 AC: 15AN: 152312Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5AN XY: 74490
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 12, 2022 | The MYH7 c.2183C>T (p.Ala728Val) missense variant results in the substitution of alanine at amino acid 728 with valine. The c.2183C>T variant that has been reported in one study, in which it was found in a heterozygous state in two individuals from a single family with hypertrophic cardiomyopathy (PMID: 11424919). Both individuals also carried a second known pathogenic missense variant in cis. The variant is reported at a frequency of 0.000395 in the Latino population of the Genome Aggregation Database. Based on the available evidence, the c.2183C>T (p.Ala728Val) variant is classified as a variant of unknown significance for hypertrophic cardiomyopathy. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 27, 2020 | This variant is associated with the following publications: (PMID: 11424919, 30297972, 28518168, 27532257, 27247418, 23820649, 25935763, 27161882, 25637381, 23299917, 24055113) - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 15, 2018 | The c.2183C>T; p.Ala728Val variant (rs121913644, ClinVar variant ID 14111) was detected and segregated with disease in a family affected with hypertrophic cardiomyopathy; however, another variant in this gene was located on the same chromosome, and was later determined to be clearly pathogenic (Blair 2001, Whiffin 2017), suggesting that the p.Ala728Val variant did not contribute to the disease. This variant is listed in the genome Aggregation Database (gnomAD) with a Latino population frequency of 0.04% (identified on 13 out of 34,420 chromosomes). The alanine at position 728 is moderately conserved, considering 12 species, and computational analyses of the effects of the p.Ala728Val variant on protein structure and function make conflicting predictions (SIFT: damaging, PolyPhen-2: benign). Based on the available information, the p.Ala728Val variant is likely to be benign. - |
Cardiomyopathy Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Oct 18, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 31, 2019 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 17, 2014 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Primary familial hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 15, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 728 of the MYH7 protein (p.Ala728Val). This variant is present in population databases (rs121913644, gnomAD 0.04%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 11424919). ClinVar contains an entry for this variant (Variation ID: 14111). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 26, 2020 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at