Submissions for variant NM_002471.4(MYH6):c.2068del (p.Leu690fs)

dbSNP: rs779614256

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001264423	SCV001442562	uncertain significance	not specified	2020-10-19	criteria provided, single submitter	clinical testing	Variant summary: MYH6 c.2068delC (p.Leu690TrpfsX38) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. The variant allele was found at a frequency of 1.2e-05 in 251444 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.2068delC in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. A co-occurrence with a pathogenic variant has been reported (MYBPC3 c.3330+5G>C; Internal testing). Evidence currently available do not allow for definitive conclusions whether loss-of-function variants in MYH6 gene cause disease. 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	RCV001880082	SCV002168216	uncertain significance	Hypertrophic cardiomyopathy 14	2023-06-25	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 984449). This variant has not been reported in the literature in individuals affected with MYH6-related conditions. This variant is present in population databases (rs779614256, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Leu690Trpfs*38) in the MYH6 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in MYH6 cause disease.
Ambry Genetics	RCV002418867	SCV002725185	uncertain significance	Cardiovascular phenotype	2023-08-22	criteria provided, single submitter	clinical testing	The c.2068delC variant, located in coding exon 16 of the MYH6 gene, results from a deletion of one nucleotide at nucleotide position 2068, causing a translational frameshift with a predicted alternate stop codon (p.L690Wfs*38). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of MYH6 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.