Submissions for variant NM_000404.4(GLB1):c.1769G>A (p.Arg590His)

gnomAD frequency: 0.00003  dbSNP: rs398123351

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000174999	SCV000226418	pathogenic	not provided	2013-11-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000794211	SCV000933605	pathogenic	Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis	2024-09-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 590 of the GLB1 protein (p.Arg590His). This variant is present in population databases (rs398123351, gnomAD 0.003%). This missense change has been observed in individuals with GM1-gangliosidosis (PMID: 8213816, 26646981). ClinVar contains an entry for this variant (Variation ID: 92901). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 8213816, 23337983). This variant disrupts the p.Arg590 amino acid residue in GLB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16941474, 17309651, 23430803). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV001804833	SCV002053883	pathogenic	Infantile GM1 gangliosidosis		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001810420	SCV002060386	likely pathogenic	GM1 gangliosidosis type 2; GM1 gangliosidosis type 3; Infantile GM1 gangliosidosis	2021-11-03	criteria provided, single submitter	clinical testing	NM_000404.2(GLB1):c.1769G>A(R590H) is a missense variant classified as likely pathogenic in the context of GLB1-related disorders. R590H has been observed in cases with relevant disease (PMID: 8213816, 27619815, Shekar_2019_(no PMID; poster), 26646981, 33737400). Functional assessments of this variant are available in the literature (PMID: 8213816, 21520340, 23337983). R590H has been observed in population frequency databases (gnomAD: SAS 0.003%). In summary, NM_000404.2(GLB1):c.1769G>A(R590H) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526614	SCV005039813	pathogenic	GM1 gangliosidosis	2024-03-18	criteria provided, single submitter	clinical testing	Variant summary: GLB1 c.1769G>A (p.Arg590His) results in a non-conservative amino acid change located in the galactose-binding domain (IPR048913) 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 249130 control chromosomes (gnomAD). c.1769G>A has been reported in the literature in individuals affected with GM1 Gangliosidosis (e.g. Boustany_1993, Regier_2016, Quaio_2020). Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated decreased enzyme activity (e.g. Boustany_1993, Higaki_2011, Takai_2013). ClinVar contains an entry for this variant (Variation ID: 92901). Based on the evidence outlined above, the variant was classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004542752	SCV005040769	pathogenic	Progressive familial intrahepatic cholestasis	2024-03-18	criteria provided, single submitter	clinical testing	Variant summary: ABCB4 c.1769G>A (p.Arg590Gln) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) 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 0.0045 in 251094 control chromosomes in the gnomAD database, including 4 homozygotes. The observed variant frequency is approximately 2.0 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCB4 causing Familial Intrahepatic Cholestasis phenotype (0.0022), strongly suggesting that the variant is benign. c.1769G>A has been reported in the literature among individuals with ABCB4-related conditions such as Anicteric Cholestasis, low phospholipid-associated cholelithiasis (LPAC), Progressive familial intrahepatic cholestasis (example, Ziol_2008, Tuan Huynh_2019, Colombo_2011, Droge_2017). These data do not allow any conclusion about variant significance. At-least one co-occurrence in cis with another presumably pathogenic variant(s) has been reported (Colombo_2011, ABCB4 c.2284G>T, p.G762X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Benign/Likely Benign, n=2; VUS, n=5). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Fulgent Genetics, Fulgent Genetics	RCV005025132	SCV005658082	likely pathogenic	GM1 gangliosidosis type 2; GM1 gangliosidosis type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis	2024-04-26	criteria provided, single submitter	clinical testing