ClinVar Miner

Submissions for variant NM_001100.3(ACTA1):c.146T>G (p.Met49Arg) (rs1553255506)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000639669 SCV000761249 pathogenic Nemaline myopathy 3 2017-12-18 criteria provided, single submitter clinical testing This sequence change replaces methionine with arginine at codon 49 of the ACTA1 protein (p.Met49Arg). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with ACTA1-related disease (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. A different missense substitution at this codon (p.Met49Val, also referred to as p.Met47Val in the literature) has been determined to be pathogenic (PMID: 19562689, 20303757). This suggests that the methionine 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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