ClinVar Miner

Submissions for variant NM_002641.4(PIGA):c.1352T>C (p.Ile451Thr)

dbSNP: rs2147714706
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Inherited Metabolic Diseases, Karolinska University Hospital RCV001374411 SCV001571357 pathogenic Multiple congenital anomalies-hypotonia-seizures syndrome 2 2021-04-12 criteria provided, single submitter clinical testing
GeneDx RCV001576089 SCV001803204 likely pathogenic not provided 2020-10-22 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); 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: 32452540, 25590979)
Invitae RCV001374411 SCV004300102 likely pathogenic Multiple congenital anomalies-hypotonia-seizures syndrome 2 2024-01-07 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 451 of the PIGA protein (p.Ile451Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of congenital disorder of glycosylation (PMID: 25590979, 32452540; Invitae). ClinVar contains an entry for this variant (Variation ID: 1064449). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PIGA protein function. 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.

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