ClinVar Genomic variation as it relates to human health

This mutation has been previously reported as disease-causing and was found once in our laboratory homozygous in a 6-month-old male with motor delays, hypotonia, plagiocephaly, dilated aortic root, partial pulmonary venous connection, pectus, club foot, hepatomegaly, T cell lymphopenia. Heterozygotes are expected to be asymptomatic carriers.

The homozygous missense variation in exon 16 of GLB1 gene that results in the amino acid substitution to cysteine for arginine at codon of 590 was detected. The variant c.1768C>T (p.Arg590Cys) has not been reported in 1000 genome and has a MAF of 0.0012% in the gnomAD database. The insilico prediction of the variant is dIsease causing by LRT, MutPred, PROVEAN and SIFT

Variant summary: GLB1 c.1768C>T (p.Arg590Cys) 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 1.2e-05 in 249130 control chromosomes (gnomAD). c.1768C>T has been reported in the literature in multiple individuals affected with GM1 gangliosidosis (example: Al-Jasmi_2012, Santamaria_2007). These data indicate that the variant is very 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 activity (Santamaria_2007). The following publications have been ascertained in the context of this evaluation (PMID: 23430803, 16941474). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 590 of the GLB1 protein (p.Arg590Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with GM1 gangliosidosis (PMID: 16941474, 17309651, 23430803). ClinVar contains an entry for this variant (Variation ID: 194596). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GLB1 function (PMID: 17664528). For these reasons, this variant has been classified as Pathogenic.