Submissions for variant NM_000257.4(MYH7):c.3734T>A (p.Leu1245Gln)

gnomAD frequency: 0.00001  dbSNP: rs397516192

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035864	SCV000059515	uncertain significance	not specified	2014-01-19	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Invitae	RCV001037116	SCV001200514	uncertain significance	Hypertrophic cardiomyopathy	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 1245 of the MYH7 protein (p.Leu1245Gln). This variant is present in population databases (rs397516192, gnomAD 0.002%). This missense change has been observed in individual(s) with dilated cardiomyopathy (DCM) (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 42971). 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.
Fulgent Genetics, Fulgent Genetics	RCV002482967	SCV002800170	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	2021-09-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003129763	SCV003815399	uncertain significance	not provided	2020-10-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003372604	SCV004087305	uncertain significance	Cardiovascular phenotype	2023-09-11	criteria provided, single submitter	clinical testing	The p.L1245Q variant (also known as c.3734T>A), located in coding exon 26 of the MYH7 gene, results from a T to A substitution at nucleotide position 3734. The leucine at codon 1245 is replaced by glutamine, an amino acid with dissimilar properties. This alteration was identified in one patient with dilated cardiomyopathy (DCM) in a large study of pathogenicity of Mendelian variants in cardiomyopathy patients, but clinical details are limited (Walsh R et al. Genet Med, 2017 Feb;19:192-203). This alteration has also been reported in exome and biobank cohorts (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 Jun;113:6701-6; Park J et al. Hum Mol Genet, 2022 Mar;31:827-837). 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.
All of Us Research Program, National Institutes of Health	RCV003996210	SCV004833005	uncertain significance	Cardiomyopathy	2024-01-08	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with glutamine at codon 1245 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 24503780, 27532257). This variant has been identified in 2/251276 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.