ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.4588C>T (p.Arg1530Ter) (rs397516225)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000758057 SCV000564453 uncertain significance Cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.4588C>T (p.Arg1530Ter) variant in MYH7 has been identified in 1 proband with cardiomyopathy (Partners LMM ClinVar SCV000059574.5). This variant has been identified in 1/66692 European chromosomes (PM2; http://exac.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 1530 leading to a truncated or absent protein; while the contribution of LOF variants in MYH7 to autosomal dominant inherited cardiomyopathy is incompletely understood, there is evidence supporting these variants as a mechanism of disease (PVS1_Moderate). In summary, 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): PM2; PVS1_Moderate
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000758057 SCV000059574 likely pathogenic Cardiomyopathy 2018-04-20 criteria provided, single submitter clinical testing The p.Arg1530X variant in MYH7 has been identified by our laboratory in trans wi th a likely pathogenic MYH7 missense variant in 2 Caucasian individuals with chi ldhood-onset DCM from 1 family. This variant has also been identified in 4/24619 0 chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadins titute.org; rs397516255). This nonsense variant leads to a premature termination codon at position 1530, which is predicted to lead to a truncated or absent pro tein. It should be noted that LOF variants in the MYH7 gene are very rare and th eir phenotypic consequences are not yet well-defined. Although heterozygous loss -of-function (LOF) variants in MYH7, such as this variant, are not believed to b e pathogenic for dominant forms of cardiomyopathy (this variant was classified a s a variant of uncertain significance in the context of autosomal dominant cardi omyopathy by the ClinGen-approved Inherited Cardiomyopathy expert panel (ClinVar SCV000564453.2), there is evidence that can they lead to severe and early onset disease when present in trans with a second MYH7 variant (LMM data). In summary , although additional studies are required to fully establish its clinical signi ficance, the p.Arg1530X variant is likely pathogenic for cardiomyopathy in an au tosomal recessive manner. ACMG/AMP Criteria applied: PVS1_Moderate; PM2; PM3.
Ambry Genetics RCV000244791 SCV000318079 uncertain significance Cardiovascular phenotype 2017-02-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000628928 SCV000749836 uncertain significance Hypertrophic cardiomyopathy 2018-02-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1530*) in the MYH7 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs397516225, ExAC 0.001%). This variant has not been reported in the literature in individuals with MYH7-related disease. ClinVar contains an entry for this variant (Variation ID: 43029). 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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000785049 SCV000923603 pathogenic MYH7-Related Disorders 2019-01-01 criteria provided, single submitter research
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000035923 SCV000280353 uncertain significance not specified 2015-04-08 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg1530Stop (R1530X; c.4588 C>T) in the MYH7 gene We classify it as a Variant of Unknown Significance (VUS). Particular caution is warranted in interpreting this truncating variant in MYH7, because a loss of function mutation in MYH7 as a mechanism for cardiopathology has not been well described. However, it is not clear that premature stop codons in the gene MYH7 typically cause disease. According to the lab, of the 410 total MYH7 alterations reported in the Human Gene Mutation Database (HGMD), only 7 are nonsense alterations leading to a premature stop codon. Furthermore, two studies in the literature show MYH7 truncating mutations failing to segregate with disease. In one study, MYH7-p.Q1334X was thought not to be disease-causing but to increase the severity of disease when a second MYH7 mutation was present. It was identified in trans with a missense MYH7 mutation in one individual with hypertrophic cardiomyopathy (HCM) and was also carried by the individual's healthy mother. The missense mutation was carried by the mildly-affected father. Likewise, the individual's affected sister carried the missense mutation but did not carry MYH7-p.Q1334X (Hougs et al. 2005 Eur J Hum Genet 13(2):161-5). In another study, MYH7-p.R54X was detected in a patient with HCM, but it did not segregate with disease in the family (Nishi et al. 1995 Circulation 91:2911-2915). In yet another study, such a variant did segregate with disease but not alone: The MYH7-p.E1455X was detected in trans with a missense MYH7 alteration and with a missense MYBPC3 alteration in a patient with HCM. The missense variants in MYH7 and MYBPC3 were detected in isolation in two unaffected individuals in this family, while the MYH7-p.E1455X variant was detected with the MYBPC3 missense variant in two other affected individuals (Girolami et al. 2010 JACC 55(14):1444-53). The p.Arg1530Stop variant was not present in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. However, there are two other premature stop variants present in the NHLBI ESP. One is a nonsense variant that has been seen in 1/4403 African American alleles. The other is a frameshift that occurred in 2/4264 African American alleles. 1000 Genomes also contains two stop gained mutations for MYH7, with dbSNP as the source: rs45620235 (E1669X) and rs141735183 (E1117X), and lists 3 frameshift variants: rs35187609, rs34856803, rs35765584.

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