Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
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, |
RCV001579503 | SCV002018195 | pathogenic | not provided | 2020-12-07 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
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, |
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 | |
Gene |
RCV001030808 | SCV001194297 | not provided | Mucopolysaccharidosis | no assertion provided | literature only | ||
Genome Diagnostics Laboratory, |
RCV001579503 | SCV001807488 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV001579503 | SCV001957326 | likely pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV001579503 | SCV001969933 | pathogenic | not provided | no assertion criteria provided | clinical testing |