Submissions for variant NM_000257.4(MYH7):c.3610G>C (p.Gly1204Arg)

gnomAD frequency: 0.00001  dbSNP: rs397516188

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035859	SCV000059510	uncertain significance	not specified	2020-05-11	criteria provided, single submitter	clinical testing	The p.Gly1204Arg variant in MYH7 has been reported in at least 1 individual with hypertrophic cardiomyopathy (LMM Data, Homberger 2016 PMID 27247418), and has also been identified in 1/112264 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 52136). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2.
Fulgent Genetics, Fulgent Genetics	RCV000765161	SCV000896390	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	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001056470	SCV001220913	uncertain significance	Hypertrophic cardiomyopathy	2021-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with arginine at codon 1204 of the MYH7 protein (p.Gly1204Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27247418). ClinVar contains an entry for this variant (Variation ID: 42966). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx	RCV001567208	SCV001790855	uncertain significance	not provided	2023-07-25	criteria provided, single submitter	clinical testing	Reported in association with HCM in the published literaure (Homburger et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27247418, 34542152)
Ambry Genetics	RCV003372603	SCV004087203	uncertain significance	Cardiovascular phenotype	2023-09-11	criteria provided, single submitter	clinical testing	The p.G1204R variant (also known as c.3610G>C), located in coding exon 25 of the MYH7 gene, results from a G to C substitution at nucleotide position 3610. The glycine at codon 1204 is replaced by arginine, an amino acid with dissimilar properties. This variant has been detected in individuals from hypertrophic cardiomyopathy cohorts, and in a cohort not selected for the presence of cardiomyopathy; however, details were limited (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 Jun;113:6701-6; Mademont-Soler I et al. PLoS One, 2017 Aug;12:e0181465; Park J et al. Hum Mol Genet, 2022 Mar;31:827-837). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.