ClinVar Miner

Submissions for variant NM_001100.3(ACTA1):c.143G>A (p.Gly48Asp) (rs367543049)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000807360 SCV000947408 pathogenic Nemaline myopathy 3 2018-12-17 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 48 of the ACTA1 protein (p.Gly48Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic 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 congenital myopathy (PMID: 27447704). This variant has also been observed in an individual affected with congenital fiber type disproportion (PMID: 19562689). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 42106). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Gly48 amino acid residue in ACTA1. Other variant(s) that disrupt this residue (p.Gly48Cys, p.Gly48Ser) have been observed in individuals with ACTA1-related conditions (PMID: 24642510, 26172852, 19562689), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
GeneReviews RCV000034933 SCV000058541 pathologic Congenital myopathy with fiber type disproportion 2013-04-11 no assertion criteria provided curation Converted during submission to Pathogenic.

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