ClinVar Miner

Submissions for variant NM_000404.4(GLB1):c.841C>T (p.His281Tyr) (rs745386663)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000667353 SCV000791787 likely pathogenic GM1 gangliosidosis type 2; Gangliosidosis GM1 type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000413217 SCV000490540 pathogenic not provided 2016-11-02 criteria provided, single submitter clinical testing The H281Y variant in the GLB1 gene has previously been reported in association with both GM1-gangliosidosis and Morquio B disease (Paschke et al., 2001; Gucev et al., 2008; Ong et al., 2012; Coutinho et al., 2012). Individuals homozygous for H281Y have been reported to have infantile onset GM1-gangliosidosis (Ong et al., 2012; Coutinho et al., 2012). The H281Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore we interpret H281Y to be a pathogenic variant.
GenomeConnect, ClinGen RCV000662341 SCV000784706 not provided Mucopolysaccharidosis, MPS-IV-B no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Invitae RCV000805468 SCV000945425 likely pathogenic Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis 2018-09-04 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 281 of the GLB1 protein (p.His281Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs745386663, ExAC 0.006%). This variant has been observed to be homozygous or in combination with another GLB1 variant in individuals affected with GM1 gangliosidosis (PMID: 11511921, 18546276, 21214877, 21497194, 22353294), and has been shown on the opposite chromosome (in trans) from a pathogenic variant in an affected individual (PMID: 15714521). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 372371). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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