Submissions for variant NM_002471.4(MYH6):c.4010C>T (p.Ser1337Leu)

gnomAD frequency: 0.00002  dbSNP: rs758922922

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000801300	SCV000941071	uncertain significance	Hypertrophic cardiomyopathy 14	2025-01-23	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 1337 of the MYH6 protein (p.Ser1337Leu). This variant is present in population databases (rs758922922, gnomAD 0.004%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 32880476). ClinVar contains an entry for this variant (Variation ID: 646916). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH6 protein function. 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	RCV001702562	SCV002003078	uncertain significance	not provided	2025-01-07	criteria provided, single submitter	clinical testing	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; Identified in a patient with DCM and a patient with LVNC who also harbored a variant in the BRAF gene (PMID: 32880476, 33049752, 34819141); This variant is associated with the following publications: (PMID: 35308086, 33049752, 35621855, 34819141, 32880476)
Ambry Genetics	RCV002352361	SCV002621125	uncertain significance	Cardiovascular phenotype	2023-12-22	criteria provided, single submitter	clinical testing	The p.S1337L variant (also known as c.4010C>T), located in coding exon 27 of the MYH6 gene, results from a C to T substitution at nucleotide position 4010. The serine at codon 1337 is replaced by leucine, an amino acid with dissimilar properties. 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001702562	SCV001932904	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001702562	SCV001955229	uncertain significance	not provided		no assertion criteria provided	clinical testing