ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.3382G>A (p.Ala1128Thr) (rs199552354)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172567 SCV000051005 likely benign not provided 2013-06-24 criteria provided, single submitter research
Center for Human Genetics,University of Leuven RCV000471337 SCV000886835 uncertain significance Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000758075 SCV000564444 uncertain significance Cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.3382G>A (p.Ala1128Thr) variant in MYH7 has been reported in 3 individuals with dilated cardiomyopathy (Partners LMM ClinVar SCV000059503.5) but has also been identified in 0.04% (4/9930) of Latino chromosomes by ExAC and is indicated as a possible low-quality site due to coverage (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.
Color RCV000758075 SCV000902575 uncertain significance Cardiomyopathy 2018-10-05 criteria provided, single submitter clinical testing
GeneDx RCV000035852 SCV000208540 uncertain significance not specified 2017-02-06 criteria provided, single submitter clinical testing p.Ala1128Thr (GCC>ACC): c.3382 G>A in exon 27 of the MYH7 gene (NM_000257.2). The A1128T variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. A1128T results in a non-conservative amino acid substitution of a non-polar Alanine with a neutral, polar Threonine at a position that is conserved in mammals. While in silico analysis predicts A1128T is benign to the protein structure/function, mutations in nearby codons (E1116K, L1135R) have been reported in association with HCM, suggesting that there is functional importance of this region of the protein. The A1128T variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in HCM,DCM-CRDM panel(s).
Invitae RCV000471337 SCV000546254 uncertain significance Hypertrophic cardiomyopathy 2018-09-06 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1128 of the MYH7 protein (p.Ala1128Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. While this variant is present in population databases (rs199552354), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in the literature in an individual affected with hypertrophic cardiomyopathy (PMID: 27247418) and in healthy individuals selected for not having personal or family history of arrhythmia, cardiomyopathy or sudden unexplained death (PMID: 23861362). ClinVar contains an entry for this variant (Variation ID: 42959). 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). In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035852 SCV000059503 likely benign not specified 2017-08-06 criteria provided, single submitter clinical testing The p.Ala1128Thr variant in MYH7 has been reported in 1 individual with DCM (Rod riguez-Garcia 2011 - abstract only). It has also been identified by our laborat ory in 2 children with DCM and 1 adult with HCM - one of the children with DCM i nherited the variant from an unaffected parent (LMM unpublished data). This vari ant has been identified in 26/236012 chromosomes in the gnomAD database (http:// gnomad.broadinstitute.org, dbSNP rs199552354). Computational prediction tools an d conservation analyses do not provide strong support for or against an impact t o the protein. In summary, given the inconsistent phenotypic observations (both DCM and HCM), 26 occurrences in the general population, and lack of disease in a carrier parent of an affected child, the clinical significance of the p.Ala1128 Thr variant is likely benign.

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