Submissions for variant NM_000257.4(MYH7):c.5559+4C>T

gnomAD frequency: 0.00005  dbSNP: rs727504319

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154409	SCV000204077	uncertain significance	not specified	2013-01-24	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV001719954	SCV000208644	likely benign	not provided	2019-12-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25351510, 20474083)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000700167	SCV000828912	uncertain significance	Hypertrophic cardiomyopathy	2024-11-25	criteria provided, single submitter	clinical testing	This sequence change falls in intron 37 of the MYH7 gene. It does not directly change the encoded amino acid sequence of the MYH7 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs727504319, gnomAD 0.007%). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25351510). ClinVar contains an entry for this variant (Variation ID: 177782). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.
Color Diagnostics, LLC DBA Color Health	RCV001183969	SCV001349828	likely benign	Cardiomyopathy	2019-07-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154409	SCV001431881	uncertain significance	not specified	2024-10-28	criteria provided, single submitter	clinical testing	Variant summary: MYH7 c.5559+4C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation 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 4.5e-05 in 245684 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MYH7 causing Cardiomyopathy (4.5e-05 vs 0.0013), allowing no conclusion about variant significance. c.5559+4C>T has been reported in the literature in individuals affected with dilated cardiomyopathy and hypertrophic cardiomyopathy without strong evidence of causality (Zimmerman_2010, Lopes_2015). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20474083, 25351510). ClinVar contains an entry for this variant (Variation ID: 177782). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002345493	SCV002649446	uncertain significance	Cardiovascular phenotype	2021-11-29	criteria provided, single submitter	clinical testing	The c.5559+4C>T intronic variant results from a C to T substitution 4 nucleotides after coding exon 35 in the MYH7 gene. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301). This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Based on available evidence to date, the clinical significance of this alteration remains unclear.