Submissions for variant NM_000257.4(MYH7):c.1407+4A>C

gnomAD frequency: 0.00001  dbSNP: rs373043783

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158804	SCV000208739	uncertain significance	not provided	2014-02-28	criteria provided, single submitter	clinical testing	c.1407+4 A>C: IVS14+4 A>C in intron 14 of the MYH7 gene (NM_000257.2). A variant of unknown significance has been identified in the MYH7 gene. The c.1407+4 A>C variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. In silico splice algorithms predict c.1407+4 A>C may negatively impact the natural splice donor site in intron 14. Splice site mutations in the MYH7 gene have been reported in association with cardiomyopathy, however, the vast majority of mutations in MYH7 are missense changes. Furthermore, various studies have conflicting hypotheses regarding MYH7 haploinsufficiency leading to cardiomyopathy (Nishi H et al., 1995; Waldmuller S et al., 2011). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in DCM-CRDM panel(s).
Invitae	RCV000694533	SCV000822983	uncertain significance	Hypertrophic cardiomyopathy	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change falls in intron 14 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 (rs373043783, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. ClinVar contains an entry for this variant (Variation ID: 181346). 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	RCV001185247	SCV001351420	uncertain significance	Cardiomyopathy	2019-07-09	criteria provided, single submitter	clinical testing	This variant is located in the splice donor region in intron 14 of the MYH7 gene. Computational splicing tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 20/282836 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Clinical significance of loss-of-function MYH7 truncations and splice variants in autosomal dominant cardiomyopathy is not clearly established. Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.