Submissions for variant NM_000404.4(GLB1):c.1783C>T (p.Arg595Trp)

gnomAD frequency: 0.00011  dbSNP: rs201807974

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000664993	SCV000789043	uncertain significance	GM1 gangliosidosis type 2; GM1 gangliosidosis type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis	2016-12-27	criteria provided, single submitter	clinical testing
Mendelics	RCV000987138	SCV001136359	uncertain significance	GM1 gangliosidosis type 2	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797774	SCV002041551	uncertain significance	not specified	2021-11-16	criteria provided, single submitter	clinical testing	Variant summary: GLB1 c.1783C>T (p.Arg595Trp) results in a non-conservative amino acid change located in the Beta-galactosidase jelly roll domain (IPR025300) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 249362 control chromosomes, predominantly at a frequency of 0.00075 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in GLB1 causing Mucopolysaccharidosis Type IVB (Morquio Syndrome B) (0.00012 vs 0.00091), allowing no conclusion about variant significance. c.1783C>T has been reported in the literature as a compound heterozygous genotype with another pathogenic allele in trans in the clinically unaffected father of an individual with GM1 gangliosidosis (Gort_2007). The disease in the affected individual was attributed to a biallelic genotype comprising the pathogenic allele from this unaffected father and another pathogenic allele from the obligate carrier mother, but not to this variant. Further biochemical workup of the healthy father revealed a pseudodeficient beta galactosidase enzyme activity in both his leukocytes and plasma. These report(s) do not provide unequivocal conclusions about association of the variant with Mucopolysaccharidosis Type IVB (Morquio Syndrome B). At least one publication reports experimental evidence evaluating an impact on protein function (Gort_2007). The most pronounced variant effect results in 33-59% of normal enzyme activity when this variant was traniently expressed in-vitro. 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 uncertain significance. Based on the evidence outlined above, the variant was classified as a pseudodeficiency allele of uncertain significance.
Invitae	RCV001868198	SCV002139718	uncertain significance	Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 595 of the GLB1 protein (p.Arg595Trp). This variant is present in population databases (rs201807974, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with GLB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 550288). 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) has been performed at Invitae 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 GLB1 protein function. Experimental studies have shown that this missense change affects GLB1 function (PMID: 17661814). 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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252200	SCV002523813	uncertain significance	See cases	2020-10-21	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2, PM3
Fulgent Genetics, Fulgent Genetics	RCV000664993	SCV002797136	uncertain significance	GM1 gangliosidosis type 2; GM1 gangliosidosis type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis	2021-12-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002532038	SCV003700998	uncertain significance	Inborn genetic diseases	2022-06-10	criteria provided, single submitter	clinical testing	The c.1783C>T (p.R595W) alteration is located in exon 16 (coding exon 16) of the GLB1 gene. This alteration results from a C to T substitution at nucleotide position 1783, causing the arginine (R) at amino acid position 595 to be replaced by a tryptophan (W). The alteration is predicted deleterious by in silico models: The p.R595W alteration is predicted to be possibly damaging by Polyphen and deleterious by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.