ClinVar Miner

Submissions for variant NM_001100.3(ACTA1):c.142G>A (p.Gly48Ser) (rs794727488)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000498534 SCV000228942 likely pathogenic not provided 2018-08-19 criteria provided, single submitter clinical testing
GeneDx RCV000498534 SCV000589828 likely pathogenic not provided 2016-05-24 criteria provided, single submitter clinical testing The G48S variant was previously reported as a de novo variant in a patient with congenital myopathy and type I fiber predominance on muscle histology (Witting et al., 2016). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G48S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and multiple missense variants at the same and in nearby residues have been reported in the Human Gene Mutation Database in association with ACTA1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000550450 SCV000638360 likely pathogenic Nemaline myopathy 3 2017-12-15 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 48 of the ACTA1 protein (p.Gly48Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (rs794727488, ExAC no frequency). This variant has been shown to arise de novo in an individual affected with congenital myopathy (PMID: 26172852). It has also been reported in an individual affected with congenital fiber type disproportion (Leiden muscular dystrophy pages, ACTA1 database) and an additional individual affected with congenital myopathy (Invitae database). ClinVar contains an entry for this variant (Variation ID: 196311). 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. A different missense substitution at this codon (p.Gly48Cys) has been determined to be likely pathogenic (PMID: 19562689, 25470062, 24642510). This suggests that the glycine 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 reported in multiple affected individuals and affects a residue that may be important for protein function. 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.

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