ClinVar Miner

Submissions for variant NM_000404.4(GLB1):c.1452C>G (p.Asn484Lys) (rs968221254)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668974 SCV000793661 uncertain significance GM1 gangliosidosis type 2; GM1 gangliosidosis type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis 2017-12-14 criteria provided, single submitter clinical testing
Invitae RCV001379670 SCV001577510 likely pathogenic Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis 2020-07-31 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 484 of the GLB1 protein (p.Asn484Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with mucopolysaccharidosis, type IVB (PMID: 12393180). ClinVar contains an entry for this variant (Variation ID: 553506). 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. 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. 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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