chr14-23416048-C-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PM1PP2PP3BP6_Very_Strong
The NM_000257.4(MYH7):c.4909G>A(p.Ala1637Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000793 in 1,614,080 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1637P) has been classified as Uncertain significance.
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.4909G>A | p.Ala1637Thr | missense_variant | 34/40 | ENST00000355349.4 | |
MHRT | NR_126491.1 | n.309C>T | non_coding_transcript_exon_variant | 3/6 | |||
MYH7 | NM_001407004.1 | c.4909G>A | p.Ala1637Thr | missense_variant | 33/39 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.4909G>A | p.Ala1637Thr | missense_variant | 34/40 | 1 | NM_000257.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000302 AC: 46AN: 152210Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251428Hom.: 1 AF XY: 0.0000368 AC XY: 5AN XY: 135896
GnomAD4 exome AF: 0.0000561 AC: 82AN: 1461870Hom.: 0 Cov.: 34 AF XY: 0.0000550 AC XY: 40AN XY: 727238
GnomAD4 genome ? AF: 0.000302 AC: 46AN: 152210Hom.: 1 Cov.: 32 AF XY: 0.000323 AC XY: 24AN XY: 74352
ClinVar
Submissions by phenotype
Cardiomyopathy Uncertain:2Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This missense variant replaces alanine with threonine at codon 1637 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 20624503, 27574918). This variant has also been identified in 25/282810 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 21, 2023 | This missense variant replaces alanine with threonine at codon 1637 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 20624503, 27574918). This variant has also been identified in 25/282810 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Oct 19, 2021 | - - |
Likely benign, reviewed by expert panel | curation | ClinGen Cardiomyopathy Variant Curation Expert Panel | Mar 22, 2021 | The c.4909G>A (p.Ala1637Thr) variant in MYH7 has been observed in 0.060% (FAF 95% CI; 22/24960) of African chromosomes in gnomAD v2.1.1 (http://gnomad.broadinstitute.org), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BS1; Kelly 2018 PMID:29300372). Additionally, computational prediction tools and conservation analysis suggest that this variant may not impact the protein (BP4). In summary, this variant meets criteria to be classified as likely benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): BS1, BP4 - |
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 09, 2020 | This variant is associated with the following publications: (PMID: 24055113, 20800588, 20624503, 23299917, 25637381, 24510615, 22958901, 23782526, 23403236, 29300372) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 16, 2023 | - - |
Dilated cardiomyopathy 1S Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Apr 30, 2021 | - - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1637 of the MYH7 protein (p.Ala1637Thr). This variant is present in population databases (rs141122361, gnomAD 0.09%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 20624503, 23782526, 27574918). ClinVar contains an entry for this variant (Variation ID: 43044). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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 familial hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | Allele frequency may indicate a low penetrance or likely benign variant - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 19, 2018 | Ala1637Thr in exon34 of MYH7: This variant is not expected to have clinical sign ificance due to a lack of evolutionary conservation of the affected amino acid ( of note, 5 mammalian species have a threonine (Thr) at this position despite hig h nearby amino acid conservation). In addition, this variant was predicted to be benign using a computational tool clinically validated by our laboratory. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011 ). It has also been identified in 5/10402 African American chromosomes by the Ex ome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs14112 2361). - |
Ventricular fibrillation Benign:1
Likely benign, criteria provided, single submitter | research | Agnes Ginges Centre for Molecular Cardiology, Centenary Institute | Nov 21, 2017 | The MYH7 Ala1637Thr variant has been previously reported in a HCM patient (Millat G et al., 2010), but has also been identified in a healthy control (Kapplinger JD, et al., 2014). We identified this variant in a proband diagnosed with idiopathic ventricular fibrillation, who has a family history of sudden death. The variant is present in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) at an allele frequency >0.000075, which is higher then expected for an inherited arrhythmia syndrome. In silico tools SIFT, PolyPhen2 and Polyphen-HCM predict this variant to be benign, however MutationTaster predicts this variant to be disease-causing. In summary, the variant is unlikely to be causing disease as it is present in the general population at an elevated frequency, has been identified in atleast 1 control and 3/4 in silico tools predict the variant to be benign, therefore we classify MYH7 Ala1637Thr as "likely benign". - |
MYH7-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 28, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 20, 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. - |
Hypertrophic cardiomyopathy 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at