ClinVar Miner

Submissions for variant NM_001100.4(ACTA1):c.617-5C>A

dbSNP: rs199804338
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen RCV004813169 SCV005438079 uncertain significance Alpha-actinopathy 2024-08-27 reviewed by expert panel curation The c.617-5C>A variant in ACTA1 is an intronic variant in the 3’ non-canonical splice site of intron 4. This variant is predicted to create a cryptic splice site, and add one amino acid (Ala) translated from intron 4 to the mature protein, but the exact impact is unknown because no functional studies have been performed. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor SpliceAI gives a score of 1 predicting an acceptor gain, which is above the threshold of 0.5, evidence that correlates with impact to ACTA1 function (PP3). This variant has been reported in two families with myopathy without muscle biopsies and three adults with features of muscle weakness (PS4_Supporting; PMID: 19562689, Invitae, SCV001556001.2, GeneDx, SCV001986137.1). The variant has been reported to segregate with myopathy in 2 affected family members from 1 family (PP1_Moderate, Invitae, SCV001556001.2). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS4_Supporting, PP1_Moderate, PM2_Supporting, PP3 (Congenital Myopathies VCEP specifications version 2; 08/27/2024).
Labcorp Genetics (formerly Invitae), Labcorp RCV001360101 SCV001556001 likely pathogenic Actin accumulation myopathy 2025-01-06 criteria provided, single submitter clinical testing This sequence change falls in intron 4 of the ACTA1 gene. It does not directly change the encoded amino acid sequence of the ACTA1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with autosomal dominant nemaline myopathy (PMID: 19562689; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1051987). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
GeneDx RCV001751704 SCV001986137 uncertain significance not provided 2021-04-19 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 19562689)
Revvity Omics, Revvity RCV001751704 SCV003822529 uncertain significance not provided 2019-08-13 criteria provided, single submitter clinical testing

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