ClinVar Miner

Submissions for variant NM_002641.3(PIGA):c.368C>T (p.Thr123Met) (rs1555945480)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000497905 SCV000589798 likely pathogenic not provided 2019-01-14 criteria provided, single submitter clinical testing The T123M variant in the PIGA gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The T123M variant was not observed in approximately 6500 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 T123M 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 where amino acids with similar properties to Threonine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in a nearby residue (R119W) has been reported in the Human Gene Mutation Database in association with PIGA-related disorder (Stenson et al., 2014), supporting the functional importance of this region of the protein. The T123M variant is a strong candidate for a pathogenic variant , however the possibility it may be a rare benign variant cannot be excluded.
Institute for Genomic Medicine (IGM) Clinical Laboratory,Nationwide Children's Hospital RCV001249629 SCV001423705 likely pathogenic Paroxysmal nocturnal hemoglobinuria 1; Multiple congenital anomalies-hypotonia-seizures syndrome 2 2018-08-16 criteria provided, single submitter clinical testing [ACMG/AMP: PM1, PM2, PP3, PP5] This alteration is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is absent from or rarely observed in large-scale population databases [PM2], is predicted to be damaging by multiple functional prediction tools [PP3], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5].

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