ClinVar Miner

Submissions for variant NM_000263.4(NAGLU):c.1927C>T (p.Arg643Cys)

gnomAD frequency: 0.00001  dbSNP: rs104894594
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001214750 SCV001386451 pathogenic Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease axonal type 2V 2023-12-18 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 643 of the NAGLU protein (p.Arg643Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 10094189, 18218046, 20852935, 26907177). ClinVar contains an entry for this variant (Variation ID: 1565). 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 NAGLU protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV001579503 SCV002018195 pathogenic not provided 2020-12-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000001631 SCV002819333 pathogenic Mucopolysaccharidosis, MPS-III-B 2022-12-08 criteria provided, single submitter clinical testing Variant summary: NAGLU c.1927C>T (p.Arg643Cys) results in a non-conservative amino acid change located in the Alpha-N-acetylglucosaminidase, C-terminal domain (IPR024732) 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 4.2e-06 in 238074 control chromosomes. c.1927C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B), and was shown to segregate with disease within families (Valstar_2010, Meijer_2016). 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, showing <10% of normal NAGLU activity in fibroblasts cells with the variant (Meijer_2017). Two laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000001631 SCV005398569 pathogenic Mucopolysaccharidosis, MPS-III-B 2023-07-17 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Mucopolysaccharidosis type IIIB (Sanfilippo B) (MIM#252920). The mechanism for Charcot-Marie-Tooth disease, axonal, type 2V (CMT; MIM#616491) is unclear. (I) 0108 - This gene is associated with both recessive and dominant disease; however, the dominant association to CMT is not well established (PanelApp, OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2, v3) <0.01 for a recessive condition (2 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated NAGLU C-terminal domain (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic multiple times, and observed in both homozygous and compound heterozygous individuals with Sanfilippo type B syndrome (ClinVar, PMID: 10094189, PMID: 20852935). (SP) 0902 - This variant has moderate evidence for segregation with disease (PMID: 20852935). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. This variant has been proven to cause reductions in enzyme activity (PMID: 28751108, PMID: 26907177). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM RCV000001631 SCV000021787 pathogenic Mucopolysaccharidosis, MPS-III-B 1999-01-01 no assertion criteria provided literature only
GeneReviews RCV001030808 SCV001194297 not provided Mucopolysaccharidosis no assertion provided literature only
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV001579503 SCV001807488 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV001579503 SCV001957326 likely pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV001579503 SCV001969933 pathogenic not provided no assertion criteria provided clinical testing

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