ClinVar Miner

Submissions for variant NM_001100.3(ACTA1):c.1123A>G (p.Lys375Glu)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000819861 SCV000960544 likely pathogenic Nemaline myopathy 3 2018-08-09 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 375 of the ACTA1 protein (p.Lys375Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with nemaline myopathy (PMID: 15336687). This variant has also been reported as p.Lys373Glu. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Variants that disrupt the p.Lys375 amino acid residue in ACTA1 have been observed in affected individuals (PMID: 11525890, 19562689, 15236405, 15138616). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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