Submissions for variant NM_003801.4(GPAA1):c.149T>A (p.Met50Lys)

gnomAD frequency: 0.00004  dbSNP: rs200581623

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001546731	SCV001766303	pathogenic	not provided	2023-12-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34703884, 37510348)
Institute of Human Genetics, University of Leipzig Medical Center	RCV001780406	SCV002026403	uncertain significance	Glycosylphosphatidylinositol biosynthesis defect 15	2021-10-11	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous with NM_003801.4:c.1477_1478del._x000D_ Criteria applied: PM3, PS4_SUP, PM2_SUP, PP3
Labcorp Genetics (formerly Invitae), Labcorp	RCV001546731	SCV002222616	uncertain significance	not provided	2023-09-25	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with congenital disorder of glycosylation (GPAA1-CDG) (PMID: 34703884). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs200581623, gnomAD 0.005%). This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 50 of the GPAA1 protein (p.Met50Lys). ClinVar contains an entry for this variant (Variation ID: 1187326). 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 GPAA1 protein function.
CeGaT Center for Human Genetics Tuebingen	RCV001546731	SCV002564027	likely pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	GPAA1: PM3:Strong, PM2
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV004596471	SCV005090818	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing