Submissions for variant NM_000257.4(MYH7):c.5560-2A>C

dbSNP: rs1566521710

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000681617	SCV000807652	likely pathogenic	MYH7-related skeletal myopathy	2018-09-13	criteria provided, single submitter	clinical testing	The variant c.5560-2A>C (NM_000257.3) in gene MYH7 causes a change at the acceptor site of consensus splicing sequence required for proper exon splicing and is located 2 basepair(s) from the exon-intron junction. The variant is not recorded in the database of populational genetic variation - dbSNP v138 and was not present among 60 thousand control subjects of the ExAC project. The variant has not yet been reported in patients with similar clinical presentation. In accordance with ACMG/AMP standards and guidelines for interpretation of sequence variants (Roberts et al. 2015) this variant is classified as a likely pathogenic variant (evidence categories: PM2, PP1-M, PP3, PP4). The identified variant in the MYH7 gene (c.5560-2A>C) has not been previously described in patients with similar phenotype, so it is not possible to conclusively assert the pathogenicity of identified finding. The following lines of evidence support the variant's pathogenicity: (1) the location in an evolutionary highly conserved gene region, (2) anticipated affect on splicing by modification of consensus splice site and the prediction of a likely effect on splicing using Human Splice Finder 3.0 tool, (3) the absence of variant from all control populations and (4) compatibility with the referred clinical presentation and autosomal dominant pattern of inheritance in the family. The identified variant in the MYH7 gene is predicted to result in in-frame deletion of exon 38 from MYH7 transcript. Variant with similar effect (skipping of exon 38) has previously been identified in patients with MYH7-related myopathies (Pajusalu et al., 2016; Fiorillo et al., 2016). Furtheremore, the segregation analysis has shown the same heterozygous variant in the MYH7 gene in the patient's affected relatives.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001199131	SCV001370126	likely pathogenic	Congenital myopathy with fiber type disproportion	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP1,PP3,PP4.