Submissions for variant NM_000257.4(MYH7):c.4519+1G>C

gnomAD frequency: 0.00001  dbSNP: rs876661374

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001854770	SCV002295848	uncertain significance	Hypertrophic cardiomyopathy	2022-03-14	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 32 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. ClinVar contains an entry for this variant (Variation ID: 235034). Disruption of this splice site has been observed in individual(s) with autosomal dominant distal myopathy and/or hypertrophic cardiomyopathy (PMID: 30297972, 32403337). This variant is not present in population databases (gnomAD no frequency).
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223846	SCV000280351	uncertain significance	not specified	2012-01-17	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. IVS32+1 G>C (cDNA nomenclature not provided) in MYH7 gene. The patient's results were re-reviewed on December 18th, 2012 and again on Jan 29, 2014. Based on the data reviewed below, we consider it a variant of uncertain significance. This is primarily because the variant is novel and because the impact of splice variants in this gene is not clear yet. This variant is novel. It has not been reported in peer reviewed literature (Google, PubMed), the LMM Sarcomere Mutation Database (Cardiogenomics) nor has it been observed in additional unrelated individuals seen at our center as of December 2012. To the best of our knowledge, only one MYH7 splice variant at the +1 position has been reported in association with cardiomyopathy. Klassen et al (2008) identified c.818+1G>A in two unrelated families (on two different haplotypes) with LVNC. In one family the variant was present in 6 affected family members with the furthest degree of relationship being 4th degree. They reported a LOD score of 2.55 for this family. In the other family the variant segregated with disease in three affected first degree relatives. RT-PCR on lymphocytes consistently revealed the normal transcript with inconsistent production of various aberrant transcripts at very low yield. I checked with the other genetic testing labs and they have each seen one MYH7 splice variant, both in patients with LVNC. Variants such as this one that affect the +1 position of the canonical splice junction consensus sequence have historically been thought to nearly always impair normal splicing. Another intronic splice variant has been associated with HCM. Hougs, L and colleagues (2005) studied 92 Danish patients with HCM for mutations in MYH7. The authors concluded that the intron variation IVS32-26 C>T seems to be over-represented among the probands (5/184 alleles, 2.7%) compared to the control group (0/200 alleles). This variation may be a genetic risk factor, however, more data are needed in order to verify significant of this observation. No additional splice variants to date (Jan 2014) have been associated with HCM to our knowledge. However, these variants have also not been observed in general population samples, including the ~6,500 individuals sequenced in the NHLBI Exome Sequencing Project. In total this variant is absent in ~6900 individuals of both Caucasian and African-American ancestry. Familion reports that the variant was absent in 400 presumably healthy individuals of mixed ancestry in their internal control population. The variant is not listed in dbSNP (as of January 2014). Additionally the variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6500 Caucasian and African American individuals (as of January 2014).