Submissions for variant NM_002641.4(PIGA):c.98A>G (p.His33Arg)

dbSNP: rs797044924

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000190762	SCV000244203	likely pathogenic	Inborn genetic diseases	2013-10-17	criteria provided, single submitter	clinical testing
Shanghai First Maternity and Infant Hospital, Tongji University	RCV001731150	SCV001981608	likely pathogenic	Multiple congenital anomalies-hypotonia-seizures syndrome 2	2021-11-02	criteria provided, single submitter	clinical testing	PM2_Supporting; PS4_Supporting; PP1; PP3; PP4 = VUS favor pathogenic
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001731150	SCV002767110	uncertain significance	Multiple congenital anomalies-hypotonia-seizures syndrome 2	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with multiple congenital anomalies-hypotonia-seizures syndrome 2 (MIM#300868). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from histidine to arginine. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 hemizygote, 0 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least three individuals, including a male with intellectual disability and epilepsy (PMID: 2915993; ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. No sufficient segregation information was provided in PMID: 29159939. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV001731150	SCV003444502	uncertain significance	Multiple congenital anomalies-hypotonia-seizures syndrome 2	2022-07-02	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 208742). This missense change has been observed in individual(s) with intellectual disability and epilepsy (PMID: 29159939). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 33 of the PIGA protein (p.His33Arg).
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003992224	SCV004810320	likely pathogenic	Paroxysmal nocturnal hemoglobinuria 1	2024-04-04	criteria provided, single submitter	clinical testing