Submissions for variant NM_000257.4(MYH7):c.5519T>C (p.Met1840Thr)

gnomAD frequency: 0.00001  dbSNP: rs149193520

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766470	SCV000279125	uncertain significance	not provided	2020-09-15	criteria provided, single submitter	clinical testing	Has not been previously published in association with MYH7-related disorders to our knowledge; Reported in ClinVar (ClinVar Variant ID# 234383; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23403236)
PreventionGenetics, part of Exact Sciences	RCV000214382	SCV000303250	likely benign	not specified		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000549508	SCV000623743	uncertain significance	Hypertrophic cardiomyopathy	2024-08-22	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1840 of the MYH7 protein (p.Met1840Thr). This variant is present in population databases (rs149193520, gnomAD 0.007%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (internal data). ClinVar contains an entry for this variant (Variation ID: 234383). An algorithm developed specifically for the MYH7 gene suggests that this missense change is likely to be deleterious (PMID: 21310275). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000214382	SCV000917843	uncertain significance	not specified	2018-09-10	criteria provided, single submitter	clinical testing	Variant summary: MYH7 c.5519T>C (p.Met1840Thr) results in a non-conservative amino acid change located in the Myosin tail (IPR002928) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 275678 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.5519T>C, has been reported in the literature in two individuals in one family affected with congenital heart defects, co-occurring with the pathogenic variant TBX5 c.709C>T (p.Arg237Trp) (Jia_2015). This report provides supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV001187338	SCV001354109	uncertain significance	Cardiomyopathy	2023-05-25	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 1840 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals in one family affected with non-syndromic congenital heart defects (PMID: 25931334); these individuals also carried a pathogenic variant in the TBX5 gene. This variant has been identified in 9/281334 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	RCV002347849	SCV002648690	uncertain significance	Cardiovascular phenotype	2023-09-14	criteria provided, single submitter	clinical testing	The p.M1840T variant (also known as c.5519T>C), located in coding exon 35 of the MYH7 gene, results from a T to C substitution at nucleotide position 5519. The methionine at codon 1840 is replaced by threonine, an amino acid with similar properties. This variant co-occurred with a variant in the TBX5 gene in affected individuals from a family with congenital heart defects (Jia Y et al. Am. J. Med. Genet. A, 2015 Aug;167A:1822-9). This variant has also been detected in an exome cohort; however, clinical details were limited (Sapp JC et al. Am. J. Hum. Genet., 2018 09;103:358-366). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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	RCV001187338	SCV004827763	uncertain significance	Cardiomyopathy	2024-08-13	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 1840 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals in one family affected with non-syndromic congenital heart defects (PMID: 25931334); these individuals also carried a pathogenic variant in the TBX5 gene. This variant has been identified in 9/281334 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.
Fulgent Genetics, Fulgent Genetics	RCV005008173	SCV005629705	uncertain significance	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2024-03-06	criteria provided, single submitter	clinical testing