Submissions for variant NM_000257.4(MYH7):c.4399C>G (p.Leu1467Val)

dbSNP: rs397516214

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158865	SCV000208800	benign	not provided	2019-05-15	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29121657, 22784669, 24953931, 25666907)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770478	SCV000901921	uncertain significance	Cardiomyopathy	2018-12-20	criteria provided, single submitter	clinical testing
Mendelics	RCV000989186	SCV001139409	uncertain significance	Hypertrophic cardiomyopathy 1	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000770478	SCV001357323	uncertain significance	Cardiomyopathy	2022-06-07	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 1467 of the MYH7 protein. Computational prediction suggests that this variant may have 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 an individual affected with multi-minicore disease and cardiomyopathy, who had a family history of early death presumed to be of cardiac origin (PMID: 22784669). This variant has also been identified in 34/251430 chromosomes (34/30616 chromosomes in South Asian) in the general population by the Genome Aggregation Database (gnomAD). Although the variant allele frequency is greater than expected for MYH7-related disorders, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035909	SCV001360974	uncertain significance	not specified	2019-04-08	criteria provided, single submitter	clinical testing	Variant summary: MYH7 c.4399C>G (p.Leu1467Val) results in a conservative amino acid change located in the Myosin tail domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 246202 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MYH7 causing Hypertrophic Cardiomyopathy (0.00014 vs 0.001), allowing no conclusion about variant significance. c.4399C>G has been reported in the literature in individuals affected with DCM, HCM, or multi-minicore disease with cardiac involvement (Lakdawala_2012, Cullup_2012, Pugh_2014, Viswanathan_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001223389	SCV001395536	uncertain significance	Hypertrophic cardiomyopathy	2023-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1467 of the MYH7 protein (p.Leu1467Val). This variant is present in population databases (rs397516214, gnomAD 0.1%). This missense change has been observed in individual(s) with MYH7-related conditions (PMID: 22464770, 22784669, 29121657). ClinVar contains an entry for this variant (Variation ID: 43015). 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.
Ambry Genetics	RCV002326731	SCV002628789	likely benign	Cardiovascular phenotype	2021-01-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Revvity Omics, Revvity	RCV000158865	SCV003817720	uncertain significance	not provided	2020-10-08	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035909	SCV000059560	uncertain significance	not specified	2014-01-17	no assertion criteria provided	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory