ClinVar Miner

Submissions for variant NM_000404.4(GLB1):c.1733A>G (p.Lys578Arg) (rs371582179)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000239412 SCV000297796 pathogenic GM1 gangliosidosis type 2 2016-07-14 criteria provided, single submitter research
Counsyl RCV000665995 SCV000790224 likely pathogenic GM1 gangliosidosis type 2; GM1 gangliosidosis type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis 2017-03-08 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000665995 SCV000894314 likely pathogenic GM1 gangliosidosis type 2; GM1 gangliosidosis type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV001061617 SCV001226365 pathogenic Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis 2019-07-31 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 578 of the GLB1 protein (p.Lys578Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs371582179, ExAC 0.006%). This variant has been observed in several individuals affected with GM1 gangliosidosis (PMID: 8213816, 21497194, 25557439). ClinVar contains an entry for this variant (Variation ID: 252985). This variant has been reported to affect GLB1 protein function (PMID: 8213816). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Lys578 amino acid residue in GLB1. Other variant(s) that disrupt this residue have been observed in individuals with GLB1-related conditions (PMID: 30267299), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV001192992 SCV001361490 pathogenic GM1 gangliosidosis 2019-03-15 criteria provided, single submitter clinical testing Variant summary: GLB1 c.1733A>G (p.Lys578Arg) results in a 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 3.7e-05 in 244112 control chromosomes (gnomAD) and has been reported in the literature in multiple individuals affected with infantile and late-infantile/juvenile GM1 gangliosidosis (Boustany_1993, Caciotti_2011, Nestrasil_2018). 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 (Caciotti_2011). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001200664 SCV001371677 pathogenic not provided 2020-06-01 criteria provided, single submitter clinical testing

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