ClinVar Miner

Submissions for variant NM_001100.3(ACTA1):c.803T>C (p.Phe268Ser) (rs1558081605)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000700123 SCV000828865 pathogenic Nemaline myopathy 3 2018-04-13 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with serine at codon 268 of the ACTA1 protein (p.Phe268Ser). The phenylalanine residue is moderately conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual with clinical features of ACTA1-related conditions (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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Phe268Leu) has been determined to be pathogenic (PMID: 23394784, 19562689). This suggests that the phenylalanine 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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