Submissions for variant NM_000257.4(MYH7):c.3245+2T>G

gnomAD frequency: 0.00001  dbSNP: rs113859723

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001269120	SCV001448364	uncertain significance	not specified	2020-11-02	criteria provided, single submitter	clinical testing	Variant summary: MYH7 c.3245+2T>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. One computational tool predicts the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. In addition, the potentially skipped exon 40 is the last exon and only encodes 5 amnio acids, thus impact of the variant on the protein function could be limited. The variant allele was found at a frequency of 4e-06 in 251394 control chromosomes. 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.3245+2T>G in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with a pathogenic variant has been reported (MYBPC3 c.2905+1G>A), providing supporting evidence for a benign role. One clinical diagnostic laboratory has 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.
Fulgent Genetics, Fulgent Genetics	RCV002491874	SCV002777442	uncertain significance	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2021-12-20	criteria provided, single submitter	clinical testing
Invitae	RCV002537710	SCV002938256	uncertain significance	Hypertrophic cardiomyopathy	2023-05-23	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 987797). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change affects a donor splice site in intron 25 of the MYH7 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in MYH7 cause disease. 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 sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486974	SCV004239454	uncertain significance	Cardiomyopathy	2022-11-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003486974	SCV004827144	uncertain significance	Cardiomyopathy	2023-06-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004649549	SCV005143080	uncertain significance	Cardiovascular phenotype	2024-04-25	criteria provided, single submitter	clinical testing	The c.3245+2T>G intronic variant results from a T to G substitution two nucleotides after coding exon 23 in the MYH7 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. However, loss of function of MYH7 has not been established as a mechanism of disease. Based on the available evidence, the clinical significance of this alteration remains unclear.