Submissions for variant NM_002471.4(MYH6):c.4781G>A (p.Arg1594Gln)

gnomAD frequency: 0.00001  dbSNP: rs146095234

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001583373	SCV001812270	uncertain significance	not provided	2019-07-25	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect
Labcorp Genetics (formerly Invitae), Labcorp	RCV001866115	SCV002276416	uncertain significance	Hypertrophic cardiomyopathy 14	2022-08-21	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1211564). This variant has not been reported in the literature in individuals affected with MYH6-related conditions. This variant is present in population databases (rs146095234, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1594 of the MYH6 protein (p.Arg1594Gln).
Ambry Genetics	RCV002334624	SCV002638193	uncertain significance	Cardiovascular phenotype	2023-01-26	criteria provided, single submitter	clinical testing	The c.4781G>A (p.R1594Q) alteration is located in exon 33 (coding exon 31) of the MYH6 gene. This alteration results from a G to A substitution at nucleotide position 4781, causing the arginine (R) at amino acid position 1594 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Mayo Clinic Laboratories, Mayo Clinic	RCV001583373	SCV004226493	uncertain significance	not provided	2022-10-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782769	SCV005394948	uncertain significance	not specified	2024-09-30	criteria provided, single submitter	clinical testing	Variant summary: MYH6 c.4781G>A (p.Arg1594Gln) results in a conservative amino acid change located in the Myosin tail domain (IPR002928) 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 1.2e-05 in 251478 control chromosomes, predominantly at a frequency of 6.2e-05 within the African or African-American subpopulation in the gnomAD database. 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.4781G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1211564). Based on the evidence outlined above, the variant was classified as uncertain significance.