Submissions for variant NM_000257.4(MYH7):c.4004C>T (p.Ser1335Leu)

gnomAD frequency: 0.00001  dbSNP: rs397516199

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035881	SCV000059532	uncertain significance	not specified	2014-04-04	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000766453	SCV000565291	uncertain significance	not provided	2018-12-18	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the MYH7 gene. The S1335L variant has reported as a variant of unknown pathogenicity, identified in 1/3200 cardiomyopathy patients (Walsh et al., 2017), though no clinical details or segregation data were provided. The S1335L variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). However, this variant has been identified in one other individual referred for HCM testing at GeneDx. Thus far, segregation data is absent for this individual due to lack of participation by informative family members. This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Thus, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae	RCV000699316	SCV000828021	uncertain significance	Hypertrophic cardiomyopathy	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1335 of the MYH7 protein (p.Ser1335Leu). This variant is present in population databases (rs397516199, gnomAD 0.006%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy or dilated cardiomyopathy (PMID: 27532257, 31918855; Invitae). ClinVar contains an entry for this variant (Variation ID: 42987). 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 with a positive predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health	RCV001189928	SCV001357322	uncertain significance	Cardiomyopathy	2023-06-15	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 1335 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 27532257, 29773157, 31983221). It has also been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257) and in an individual affected with left ventricular noncompaction (PMID: 31918855). This variant has been identified in 10/249760 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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	RCV002371825	SCV002624520	uncertain significance	Cardiovascular phenotype	2020-02-14	criteria provided, single submitter	clinical testing	The p.S1335L variant (also known as c.4004C>T), located in coding exon 28 of the MYH7 gene, results from a C to T substitution at nucleotide position 4004. The serine at codon 1335 is replaced by leucine, an amino acid with dissimilar properties. This variant has been detected in dilated and hypertrophic cardiomyopathy cohorts; however, details were limited (Walsh R et al. Genet. Med., 2017 02;19:192-203; Ware JS et al. J. Am. Coll. Cardiol., 2018 05;71:2293-2302). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002477073	SCV002783965	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	2021-08-09	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001189928	SCV003838104	uncertain significance	Cardiomyopathy	2022-04-20	criteria provided, single submitter	clinical testing