ClinVar Miner

Submissions for variant NM_002641.4(PIGA):c.368C>T (p.Thr123Met)

dbSNP: rs1555945480
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000497905 SCV000589798 pathogenic not provided 2022-04-06 criteria provided, single submitter clinical testing Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32371413, 32980267, 31704190, 32452540)
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].
Labcorp Genetics (formerly Invitae), Labcorp RCV001341771 SCV001535662 uncertain significance Multiple congenital anomalies-hypotonia-seizures syndrome 2 2023-08-27 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PIGA protein function. This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 123 of the PIGA protein (p.Thr123Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of PIGA-related conditions (PMID: 31704190, 32452540). ClinVar contains an entry for this variant (Variation ID: 432113).

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