Submissions for variant NM_000257.4(MYH7):c.1358G>T (p.Arg453Leu)

dbSNP: rs397516101

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000818531	SCV000959150	likely pathogenic	Hypertrophic cardiomyopathy	2022-09-19	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg453 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11133230, 12975413, 17599605, 24093860, 24111713; 20031618 23283745). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function. ClinVar contains an entry for this variant (Variation ID: 235026). This missense change has been observed in individual(s) with clinical features of MYH7-related conditions (PMID: 21520333). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 453 of the MYH7 protein (p.Arg453Leu).
Ambry Genetics	RCV002378957	SCV002691793	likely pathogenic	Cardiovascular phenotype	2022-04-25	criteria provided, single submitter	clinical testing	The p.R453L variant (also known as c.1358G>T), located in coding exon 12 of the MYH7 gene, results from a G to T substitution at nucleotide position 1358. The arginine at codon 453 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; Harper AR et al. Nat Genet, 2021 02;53:135-142). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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). In addition, other alterations affecting the same amino acid, p.R453C, p.R453H and p.R453S have been reported in association with HCM (Frazier A et al. Pediatr Cardiol, 2008 Jul;29:846-50; Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223878	SCV000280300	uncertain significance	not specified	2015-06-02	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.Arg453Leu in MYH7 Based on the lack of data on this variant, we consider it a variant of uncertain significance. The online cardiogenomics database (curated by the Seidman group) notes that this variant was reported online by Haluza et al in 2000. I wasn’t able to find any further details or additional reports. The arginine at codon 453 is conserved across species, as are neighboring variants. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. There are two other variants at this codon (p.Arg453Cys, p.Arg453His). There is strong evidence supporting the pathogenicity of p.Arg453Cys and we consider it very likely disease causing. We currently classify p.Arg453His as likely disease causing. Variants at a nearby codon have been reported in association with cardiomyopathy (p.Lys450Glu, p.Lys450Thr). There is no variation at codon 453 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~5000 Caucasian and African American individuals (as of 1/14/2012). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 1/14/2012). ***The variant was not observed in published controls: ***.