Submissions for variant NM_000257.4(MYH7):c.611G>T (p.Arg204Leu)

dbSNP: rs397516260

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154508	SCV000204179	uncertain significance	not specified	2014-04-17	criteria provided, single submitter	clinical testing	The Arg204Leu variant in MYH7 has not been reported in the literature, but has b een identified by our laboratory in 4 Caucasian individuals with HCM, one of who m also carried another variant of unknown significance in MYBPC3. This variant h as not been identified in large European American and African American populatio ns by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS); oth er populations have not been examined adequately. Arginine (Arg) at this positio n is conserved in mammals and chickens, but this part of the MYH7 protein appear s to be less well conserved in more distantly related species. In addition, this variant was predicted to be benign using a computational tool clinically valida ted by our laboratory. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011). While the presence in multiple affected individua ls and absence from the general population are consistent with a role in disease , the computational data suggest that the variant may not impact the normal func tion of the protein. In summary, additional information is needed to fully asses s the clinical significance of the Arg204Leu variant.
GeneDx	RCV000724202	SCV000208685	likely pathogenic	not provided	2023-05-10	criteria provided, single submitter	clinical testing	Reported in association with cardiomyopathy and unexplained cardiac arrest (Walsh et al., 2017; Hathaway et al., 2021; Grondin et al., 2022); however, details regarding clinical presentation, segregation data, and other co-occurring variants were not provided; Reported in a patient with erythropoietic porphyria who underwent exome sequencing (Wang et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24111713, 27247418, 27841901, 21310275, 12707239, 33673806, 27532257, 35352813, 29300372, 26338694)
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000416304	SCV000485049	likely pathogenic	Cardiomyopathy	2016-05-18	criteria provided, single submitter	clinical testing
Invitae	RCV000628899	SCV000749807	pathogenic	Hypertrophic cardiomyopathy	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 204 of the MYH7 protein (p.Arg204Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 177869). An algorithm developed specifically for the MYH7 gene suggests that this missense change is likely to be tolerated (PMID: 21310275). This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV000724202	SCV000928265	likely pathogenic	not provided	2019-03-06	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000416304	SCV003838520	likely pathogenic	Cardiomyopathy	2023-01-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003362694	SCV004084724	likely pathogenic	Cardiovascular phenotype	2023-07-17	criteria provided, single submitter	clinical testing	The p.R204L variant (also known as c.611G>T), located in coding exon 5 of the MYH7 gene, results from a G to T substitution at nucleotide position 611. The arginine at codon 204 is replaced by leucine, an amino acid with dissimilar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This variant has been detected in four individuals from a hypertrophic cardiomyopathy (HCM) genetic testing cohort; however, clinical details were limited (Walsh R et al. Genet Med, 2017 02;19:192-203). Another alteration at the same codon, p.R204H (c.611G>A), has also been reported in association with HCM (Richard P et al. Circulation. 2003). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
All of Us Research Program, National Institutes of Health	RCV000628899	SCV004830150	likely pathogenic	Hypertrophic cardiomyopathy	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 204 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 27532257, 35352813, communication with external laboratories: SCV000749807.7, SCV000208685.13). It. has also been reported in an individual affected with sudden cardiac death and suspected cardiomyopathy (PMID: 35352813). A different variant occurring at the same codon, p.Arg204His, is a considered to be disease-causing (Clinvar variation ID: 43095), indicating that arginine at this position is important for MYH7 protein function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Eurofins Ntd Llc (ga)	RCV000724202	SCV000231502	uncertain significance	not provided	2015-12-03	flagged submission	clinical testing