Submissions for variant NM_000257.4(MYH7):c.2377C>T (p.Arg793Ter)

dbSNP: rs140175704

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000696757	SCV000825334	uncertain significance	Hypertrophic cardiomyopathy	2022-05-02	criteria provided, single submitter	clinical testing	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: 574743). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg793*) 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.
Color Diagnostics, LLC DBA Color Health	RCV001176909	SCV001341009	uncertain significance	Cardiomyopathy	2023-09-01	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 21 of the MYH7 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with acute myocarditis (PMID: 34368507). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function MYH7 truncation variants in autosomal dominant cardiovascular disorders is not clearly established. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002458259	SCV002735914	uncertain significance	Cardiovascular phenotype	2021-03-19	criteria provided, single submitter	clinical testing	The p.R793* variant (also known as c.2377C>T), located in coding exon 19 of the MYH7 gene, results from a C to T substitution at nucleotide position 2377. This changes the amino acid from an arginine to a stop codon within coding exon 19. This alteration is expected to result in premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of MYH7 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV002510962	SCV002820741	uncertain significance	not provided	2023-01-10	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235359	SCV003934396	uncertain significance	not specified	2023-05-05	criteria provided, single submitter	clinical testing	Variant summary: MYH7 c.2377C>T (p.Arg793X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay in a gene where molecular mechanism of disease is gain of function. The variant was absent in 251466 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2377C>T has been reported in the literature in an individual affected with acute myocarditis and the authors classifed the variant as VUS (example:Kontorovich_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34368507). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.