ClinVar

Description

Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.808G nucleotide in the ACTA1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 12921789, 15226407, 21514153). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant is also known as G268S. This missense change has been observed in individual(s) with autosomal dominant nemaline myopathy and/or clinical features of nemaline myopathy (PMID: 15138616, 19562689). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 270 of the ACTA1 protein (p.Gly270Ser). This variant also falls at the last nucleotide of exon 5, which is part of the consensus splice site for this exon.