Submissions for variant NM_002641.4(PIGA):c.242G>A (p.Arg81His)

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Minimum conflict level: Report conflict between different conditions
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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001055034	SCV001219398	likely pathogenic	Multiple congenital anomalies-hypotonia-seizures syndrome 2	2025-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 81 of the PIGA protein (p.Arg81His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of multiple congenital anomalies hypotonia seizures syndrome (PMID: 29310717, 32452540; internal data). ClinVar contains an entry for this variant (Variation ID: 850786). Invitae Evidence 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 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. This variant disrupts the p.Arg81 amino acid residue in PIGA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25326635, 32220244, 33763700). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001055034	SCV002818577	likely pathogenic	Multiple congenital anomalies-hypotonia-seizures syndrome 2	2023-01-11	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV005232088	SCV005872405	likely pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing

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