Submissions for variant NM_002471.4(MYH6):c.5660C>T (p.Ala1887Val)

gnomAD frequency: 0.00002  dbSNP: rs767096302

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000617320	SCV000740181	uncertain significance	Cardiovascular phenotype	2023-10-27	criteria provided, single submitter	clinical testing	The p.A1887V variant (also known as c.5660C>T), located in coding exon 35 of the MYH6 gene, results from a C to T substitution at nucleotide position 5660. The alanine at codon 1887 is replaced by valine, an amino acid with similar 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194284	SCV001363685	uncertain significance	not specified	2019-03-21	criteria provided, single submitter	clinical testing	Variant summary: MYH6 c.5660C>T (p.Ala1887Val) results in a non-conservative amino acid change located in the Myosin tail domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant is also located at the second to last 3' position of exon 37 and 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.8e-05 in 277100 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.5660C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
AiLife Diagnostics, AiLife Diagnostics	RCV002223888	SCV002502958	uncertain significance	not provided	2021-11-09	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002491335	SCV002776845	uncertain significance	Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to	2021-07-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002532818	SCV002975776	uncertain significance	Hypertrophic cardiomyopathy 14	2023-03-27	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1887 of the MYH6 protein (p.Ala1887Val). This variant is present in population databases (rs767096302, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with MYH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 520363). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
PreventionGenetics, part of Exact Sciences	RCV004533290	SCV004117726	uncertain significance	MYH6-related disorder	2023-08-13	criteria provided, single submitter	clinical testing	The MYH6 c.5660C>T variant is predicted to result in the amino acid substitution p.Ala1887Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-23852435-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.