ClinVar Miner

Submissions for variant NM_001100.3(ACTA1):c.808G>C (p.Gly270Arg) (rs121909525)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000217314 SCV000271203 pathogenic Neuromuscular Diseases 2018-12-21 criteria provided, single submitter clinical testing The p.Gly270Arg variant in ACTA1 (also known as p.Gly268Arg) has been previously reported in at least 4 individuals with nemaline myopathy, including 2 confirme d de novo occurrences (Sparrow 2003, Laing 2009, LMM data). It was absent from l arge population studies. Several different variants at this position have occurr ed de novo in children with nemaline myopathy (p.Gly270Asp, p.Gly270Cys, and p.G ly270Ser; reported as p.Gly268Asp, p.Gly268Cys, and p.Gly268Ser; Ilkovski 2001, Graziano 2004, Ohlsson 2004, Laing 2009), supporting that changes at this codon are not tolerated. In vitro functional studies and structural analysis of the pr otein support an impact on protein function (Costa 2004, Bathe 2007, von der Eck en 2015). In addition, this variant is located last three bases of the exon, whi ch is part of the 5? splice region and computational tools suggest a possible im pact to splicing. In summary, this variant meets criteria to be classified as pa thogenic for autosomal dominant nemaline myopathy. ACMG/AMP Criteria applied: P M5_Strong, PM6_Strong, PS4_Moderate, PS3_Moderate, PP3.
Invitae RCV000558844 SCV000638378 pathogenic Nemaline myopathy 3 2017-06-30 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 270 of the ACTA1 protein (p.Gly270Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant also falls at the last nucleotide of exon 5 of the ACTA1 coding sequence, which is part of the consensus splice site for this exon. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with nemaline myopathy (PMID: 12921789, 15226407, 21514153). This variant is also known as Gly268Arg in the literature. ClinVar contains an entry for this variant (Variation ID: 228243). Experimental studies do not agree on the impact of this missense change. One study reports this sequence change behaves similar to wild type (PMID: 17227580) while another study reports this change impairs polymerization (PMID: 15226407). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. A different missense substitution at this codon (p.Gly270Cys, also reported as p.Gly268Cys) has been determined to be pathogenic (PMID: 12921789, 15226407, 15198992, 11333380). This suggests that the glycine residue is critical for ACTA1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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