Submissions for variant NM_000404.4(GLB1):c.145C>T (p.Arg49Cys)

gnomAD frequency: 0.00001  dbSNP: rs72555358

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000672371	SCV000797470	likely pathogenic	GM1 gangliosidosis type 2; GM1 gangliosidosis type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis	2018-01-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000707313	SCV000836403	pathogenic	Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis	2022-10-27	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs72555358, gnomAD 0.01%). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg49 amino acid residue in GLB1. Other variant(s) that disrupt this residue have been observed in individuals with GLB1-related conditions (PMID: 15986423, 30267299), which suggests that this may be a clinically significant amino acid residue. 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 GLB1 protein function. ClinVar contains an entry for this variant (Variation ID: 923). This missense change has been observed in individual(s) with GM1-gangliosidosis (PMID: 15365997, 21520340, 25936995, 26646981; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 49 of the GLB1 protein (p.Arg49Cys).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778644	SCV002015131	pathogenic	Mucopolysaccharidosis, MPS-IV-B	2021-10-30	criteria provided, single submitter	clinical testing	Variant summary: GLB1 c.145C>T (p.Arg49Cys) results in a non-conservative amino acid change located in the Glycoside hydrolase 35, catalytic domain (IPR031330) of 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 1.2e-05 in 249536 control chromosomes. c.145C>T has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IVB (Morquio Syndrome B) and short stature (example, Huang_2018, Bidchol_2015, Georgiou_2004). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal Beta-D galactosidase activity in a homozygous individual (example Bidchol_2015). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000000971	SCV002754480	likely pathogenic	Infantile GM1 gangliosidosis		criteria provided, single submitter	clinical testing	A Homozygous missense variation in exon 2 of the GLB1 gene that results in the amino acid substitution of Cysteine for Arginine at codon 49 was detected. The observed variant c.145C>T (p.Arg49Cys) has not been reported in the 1000 genomes and has MAF of 0.001% in gnomAD databases. The in silico prediction of the variant is disease causing by PolyPhen-2 (HumDiv), SIFT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic.
OMIM	RCV000000971	SCV000021121	pathogenic	Infantile GM1 gangliosidosis	1991-09-01	no assertion criteria provided	literature only
Eurofins Ntd Llc (ga)	RCV000175599	SCV000227114	uncertain significance	not provided	2014-06-24	flagged submission	clinical testing