Submissions for variant NM_002471.4(MYH6):c.4651-3C>A

gnomAD frequency: 0.00009  dbSNP: rs572175190

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232303	SCV000287430	uncertain significance	Hypertrophic cardiomyopathy 14	2024-12-24	criteria provided, single submitter	clinical testing	This sequence change falls in intron 32 of the MYH6 gene. It does not directly change the encoded amino acid sequence of the MYH6 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs572175190, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MYH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 239176). 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.
GeneDx	RCV000599110	SCV000710492	uncertain significance	not provided	2018-01-30	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the MYH6 gene. The c.4651-3 C>A variant has not been published as pathogenic or been reported as benign to our knowledge. The c.4651-3 C>A variant is observed in 7/9634 (0.07%) alleles from individuals of Ashkenazi Jewish background and in 45/271634 (0.02%) global alleles in large population cohorts (Lek et al., 2016). This substitution occurs at a nucleotide that is not conserved. In-silico splice algorithms are inconclusive as to whether this variant impacts the natural splice acceptor site in intron 32 and results in abnormal gene splicing. In the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined.
Baylor Genetics	RCV000232303	SCV001524357	uncertain significance	Hypertrophic cardiomyopathy 14	2019-07-25	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Ambry Genetics	RCV002338721	SCV002636817	uncertain significance	Cardiovascular phenotype	2023-08-11	criteria provided, single submitter	clinical testing	The c.4651-3C>A intronic variant results from a C to A substitution 3 nucleotides before coding exon 31 in the MYH6 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000599110	SCV001741514	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000599110	SCV001958016	likely benign	not provided		no assertion criteria provided	clinical testing