Submissions for variant NM_000404.4(GLB1):c.175C>T (p.Arg59Cys)

gnomAD frequency: 0.00002  dbSNP: rs756878418

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000597388	SCV000700521	pathogenic	not provided	2017-03-03	criteria provided, single submitter	clinical testing
Counsyl	RCV000669165	SCV000793885	likely pathogenic	GM1 gangliosidosis type 2; GM1 gangliosidosis type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis	2017-09-11	criteria provided, single submitter	clinical testing
Mendelics	RCV000987141	SCV001136362	pathogenic	GM1 gangliosidosis type 2	2019-05-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001050379	SCV001214482	pathogenic	Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis	2024-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 59 of the GLB1 protein (p.Arg59Cys). This variant is present in population databases (rs756878418, gnomAD 0.04%). This missense change has been observed in individual(s) with GM1 gangliosidosis (PMID: 15714521, 16941474, 17309651). ClinVar contains an entry for this variant (Variation ID: 496895). 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) indicates that this missense variant is expected to disrupt GLB1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GLB1 function (PMID: 15714521). This variant disrupts the p.Arg59 amino acid residue in GLB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10338095, 16941474, 17309651, 17664528). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002245028	SCV002512228	pathogenic	Infantile GM1 gangliosidosis	2021-07-27	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 moderate, PM2 moderate, PM3 strong, PP3 supporting, PP4 supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005240291	SCV005884965	pathogenic	GM1 gangliosidosis	2024-12-20	criteria provided, single submitter	clinical testing	Variant summary: GLB1 c.175C>T (p.Arg59Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 249480 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GLB1 causing GM1 Gangliosidosis (4.8e-05 vs 0.00091), allowing no conclusion about variant significance. c.175C>T has been reported in the literature in individuals affected with GM1 Gangliosidosis (e.g. Caciotti_2005, Santamaria_2006, 2007). These data indicate that the variant is likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.176G>A, p.Arg59His), supporting the critical relevance of codon 59 to GLB1 protein function. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant rendered GLB1 enzymatically inactive (Caciotti_2005). The following publications have been ascertained in the context of this evaluation (PMID: 15714521, 16941474, 17309651). ClinVar contains an entry for this variant (Variation ID: 496895). Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000597388	SCV001797803	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000597388	SCV001956633	pathogenic	not provided		no assertion criteria provided	clinical testing