ClinVar Miner

Submissions for variant NM_000404.4(GLB1):c.994G>A (p.Asp332Asn)

gnomAD frequency: 0.00002  dbSNP: rs781658798
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001383879 SCV001583193 pathogenic Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis 2023-09-12 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GLB1 function (PMID: 10839995, 10841810, 18353697). 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: 1071414). This missense change has been observed in individual(s) with GM1 gangliosidosis (PMID: 10839995, 19472408, 21497194, 25936995). This variant is present in population databases (rs781658798, gnomAD 0.004%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 332 of the GLB1 protein (p.Asp332Asn).
GeneDx RCV003327516 SCV004034904 pathogenic not provided 2024-03-04 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect; enzymatic activity assays showed <1% residual activity (PMID: 10839995); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25525159, 21497194, 10839995, 18353697)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004690099 SCV005185658 pathogenic GM1 gangliosidosis 2024-05-16 criteria provided, single submitter clinical testing Variant summary: GLB1 c.994G>A (p.Asp332Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249530 control chromosomes. c.994G>A has been reported in the literature in individuals affected with GM1 Gangliosidosis (e.g. Zhang_2000, Bidchol_2015, Caciotti_2011). 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, finding that the variant results in <1% of enzymatic activity (Zhang_2000). The following publications have been ascertained in the context of this evaluation (PMID: 10839995, 21497194, 25936995). ClinVar contains an entry for this variant (Variation ID: 1071414). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV005038188 SCV005658097 pathogenic GM1 gangliosidosis type 2; GM1 gangliosidosis type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis 2024-05-17 criteria provided, single submitter clinical testing

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