ClinVar Miner

Submissions for variant NM_000263.4(NAGLU):c.1562C>T (p.Pro521Leu) (rs104894595)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001043674 SCV001207432 pathogenic Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease, axonal type 2V 2020-10-13 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 521 of the NAGLU protein (p.Pro521Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs104894595, ExAC 0.005%). This variant has been observed to segregate with mucopolysaccharidosis type III in families (PMID: 20852935, 9443875) and has also been observed in individuals affected with mucopolysaccharidosis type III (PMID: 28306536) ClinVar contains an entry for this variant (Variation ID: 1566). 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: Probably Damaging; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000001632 SCV001362135 pathogenic Mucopolysaccharidosis, MPS-III-B 2019-02-13 criteria provided, single submitter clinical testing Variant summary: NAGLU c.1562C>T (p.Pro521Leu) results in a non-conservative amino acid change located in the C-terminal domain 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 2.6e-05 in 271726 control chromosomes (gnomAD). c.1562C>T has been reported in the literature in compound heterozygous and homozygous individuals affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B) (e.g. Zhao 1998, Beesley 2005, Valstar 2010). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000001632 SCV000021788 pathogenic Mucopolysaccharidosis, MPS-III-B 1999-01-01 no assertion criteria provided literature only
SingHealth Duke-NUS Institute of Precision Medicine RCV000001632 SCV000853170 uncertain significance Mucopolysaccharidosis, MPS-III-B 2017-06-07 no assertion criteria provided curation
GeneReviews RCV001030807 SCV001194296 pathogenic Mucopolysaccharidosis 2019-09-04 no assertion criteria provided literature only

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