Submissions for variant NM_000257.4(MYH7):c.745C>T (p.Arg249Ter)

dbSNP: rs730880852

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000472959	SCV000546220	uncertain significance	Hypertrophic cardiomyopathy	2021-08-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg249*) 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. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. 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.
Fulgent Genetics, Fulgent Genetics	RCV002481417	SCV002803899	uncertain significance	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2021-11-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003532128	SCV004356969	uncertain significance	Cardiomyopathy	2024-09-09	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 9 of the MYH7 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with left ventricular non-compaction (PMID: 28798025). This variant has been identified in 1/251458 chromosomes 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.
All of Us Research Program, National Institutes of Health	RCV003532128	SCV004822528	uncertain significance	Cardiomyopathy	2024-06-09	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 9 of the MYH7 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with left ventricular non-compaction (PMID: 28798025). This variant has been identified in 1/251458 chromosomes 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV003532128	SCV004848035	likely pathogenic	Cardiomyopathy	2019-02-08	criteria provided, single submitter	clinical testing	The p.Arg249X variant in MYH7 has been reported in one individual with left ventricular non-compaction (Miszalski-Jamka 2017). It has also been identified in 1/113734 European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID 407183). This nonsense variant leads to a premature termination codon at position 249, which is predicted to lead to a truncated or absent protein. Although heterozygous loss-of-function (LOF) variants in MYH7 are not believed to be pathogenic for autosomal dominant forms of cardiomyopathy, 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 significance, the p.Arg249X variant is likely pathogenic for cardiomyopathy in an autosomal recessive manner. ACMG/AMP Criteria applied: PVS1, PM2.