ClinVar Miner

Submissions for variant NM_001100.3(ACTA1):c.616G>A (p.Ala206Thr) (rs1057521119)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000418889 SCV000521129 likely pathogenic not provided 2016-11-08 criteria provided, single submitter clinical testing The c.616 G>A variant has been previously reported as a heterozygous variant in association with ACTA1-related disorders (Laing et al., 2009). 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. Multiple in silico algorithms predict that c.616 G>A may damage or destroy the natural splice donor site of intron 4 and alter gene splicing. However, in the absence of RNA/functional studies the actual effect of c.616 G>A on splicing in this individual is unknown. If c.616 G>A does not alter splicing, it will result in the A206T missense change. The A206T 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 missense variants in nearby residues (T204I; E207G/D; E209D) 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. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function.
Invitae RCV000802023 SCV000941830 pathogenic Nemaline myopathy 3 2018-10-23 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 206 of the ACTA1 protein (p.Ala206Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant also falls at the last nucleotide of exon 4 of the ACTA1 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several families affected with nemaline myopathy (PMID: 19562689). ClinVar contains an entry for this variant (Variation ID: 381641). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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