ClinVar Miner

Submissions for variant NM_001100.3(ACTA1):c.402G>A (p.Met134Ile) (rs1553255486)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000528006 SCV000638364 likely pathogenic Nemaline myopathy 3 2017-03-29 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 134 of the ACTA1 protein (p.Met134Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with typical nemaline myopathy (PMID: 19562689). This variant has been seen to segregate with nemaline rod myopathy in a single family (Invitae). 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 tolerated, but these predictions have not been confirmed by published functional studies. A different missense substitution at this codon (p.Met134Val, also known as p.Met132Val) has been determined to be likely pathogenic (PMID: 19562689, 10508519, 15226407, 14733965). This suggests that the methionine residue is critical for ACTA1 protein function and that other missense substitutions at this position may also be pathogenic. In summary, this variant is a rare missense change that has been observed in an affected individual and segregates in a single family with ACTA1 related conditions. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000658552 SCV000780328 likely pathogenic not provided 2018-02-28 criteria provided, single submitter clinical testing

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