ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.457del (p.His153fs)

dbSNP: rs397516224
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel RCV001727521 SCV001976479 uncertain significance Cardiomyopathy 2021-08-25 reviewed by expert panel curation The c.457del (p.His153Thrfs*14) variant in MYH7 has been identified in a 6 month old with DCM that also had a second variant in MYH7 (LMM pers comm) as well as 2 cases in the literature without clinical information (Ceyhan-Birsoy 2019 PMID: 30609409; Zimmerman 2010 PMID: 20474083), which is insufficient to apply PS4_Supporting. This variant has been identified in 0.000879% (1/113760) of European (Non-Finnish) chromosomes in gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift leading to a truncated or absent protein and the contribution of LOF variants in MYH7 to autosomal dominant inherited cardiomyopathy is incompletely understood. In summary, due to a lack of evidence, this variant is classified as uncertain significance for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000035922 SCV000059573 likely pathogenic Primary dilated cardiomyopathy 2016-04-06 criteria provided, single submitter clinical testing The p.His153ThrfsX14 variant in MYH7 has been identified in one individual with cardiomyopathy (in trans with another MYH7 variant) but has not been observed in large population studies. This variant is predicted to cause a frameshift, whic h alters the protein?s amino acid sequence beginning at position 153 and leads t o a premature termination codon 14 amino acids downstream. This alteration is th en predicted to lead to a truncated or absent protein. Although heterozygous los s-of-function (LOF) variants in MYH7, such as this variant, are not believed to be pathogenic for the dominant condition more classically associated to MYH7, wh en a LOF variant is found in trans with another variant affecting function, a mo re severe and early-onset cardiomyopathy presentation can occur (LMM unpublished data). It should be noted that loss of function variants in the MYH7 gene are very rare and therefore an understanding of their potential impact is not well s tudied. In summary, this variant leads to a predicted loss-of-function of the pr otein and, although additional studies are required to fully establish its clini cal significance, it is likely pathogenic for a recessive presentation.
Invitae RCV000820956 SCV000961695 uncertain significance Hypertrophic cardiomyopathy 2022-07-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.His153Thrfs*14) in the MYH7 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in MYH7 cause disease. 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. ClinVar contains an entry for this variant (Variation ID: 43028). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 20474083). This variant is present in population databases (rs397516224, gnomAD 0.0009%).

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