ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.4909G>A (p.Ala1637Thr) (rs141122361)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000758026 SCV000564454 uncertain significance Cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.4909G>A (p.Ala1637Thr) variant in MYH7 has been reported in 2 individuals with cardiomyopathy (PMID:20624503; Partners LMM ClinVar SCV000059589.5) but has also been identified in 0.048% (5/10402) of African chromosomes by ExAC (http://exac.broadinstitute.org). Since the MYH7 specifications state that PS4 is only applicable if a variant is absent or rare in large population studies, PS4 criterion was not applied (PMID:29300372). In summary, due to lack of evidence, this variant meets criteria to be classified as uncertain significance for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): No criteria applied.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035938 SCV000059589 likely benign not specified 2018-07-19 criteria provided, single submitter clinical testing 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).
CSER_CC_NCGL; University of Washington Medical Center RCV000148696 SCV000190425 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-06-01 criteria provided, single submitter research Allele frequency may indicate a low penetrance or likely benign variant
GeneDx RCV000035938 SCV000208612 uncertain significance not specified 2017-05-26 criteria provided, single submitter clinical testing The A1637T variant of uncertain significance in the MYH7 gene has been previously reported in two unrelated individuals with HCM (Millat et al., 2010; Núñez et al., 2013). However, A1637T has been reported in 1 of 427 ostensibly healthy published control individuals (Kapplinger et al., 2014) and has also been observed in 0.08% (21/24024) of alleles from individuals of African ancestry in large population cohorts (Lek et al., 2016). Moreover, this substitution occurs at a position that is not conserved across species, and threonine (T) is the wild-type amino acid at this position in at least one mammalian species. Nevertheless, A1637T is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000465008 SCV000546282 uncertain significance Hypertrophic cardiomyopathy 2018-09-26 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1637 of the MYH7 protein (p.Ala1637Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs141122361, ExAC 0.05%). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 20624503, 23782526, 27574918). ClinVar contains an entry for this variant (Variation ID: 43044). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be tolerated. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000620929 SCV000735725 uncertain significance Cardiovascular phenotype 2016-06-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000853439 SCV000996350 likely benign Ventricular fibrillation 2017-11-21 criteria provided, single submitter research

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