rs569519789
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_000263.4(NAGLU):āc.1487T>Cā(p.Leu496Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000656 in 152,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L496L) has been classified as Likely benign.
Frequency
Consequence
NM_000263.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NAGLU | NM_000263.4 | c.1487T>C | p.Leu496Pro | missense_variant | 6/6 | ENST00000225927.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NAGLU | ENST00000225927.7 | c.1487T>C | p.Leu496Pro | missense_variant | 6/6 | 1 | NM_000263.4 | P1 | |
NAGLU | ENST00000591587.1 | c.*456T>C | 3_prime_UTR_variant | 4/4 | 5 | ||||
NAGLU | ENST00000592454.1 | c.*330T>C | 3_prime_UTR_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152256Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000130 AC: 3AN: 230624Hom.: 0 AF XY: 0.00000794 AC XY: 1AN XY: 125960
GnomAD4 exome Cov.: 32
GnomAD4 genome ? AF: 0.00000656 AC: 1AN: 152374Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74512
ClinVar
Submissions by phenotype
Mucopolysaccharidosis, MPS-III-B Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 18, 2023 | Variant summary: NAGLU c.1487T>C (p.Leu496Pro) results in a non-conservative amino acid change located in the Alpha-N-acetylglucosaminidase, C-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.3e-05 in 230624 control chromosomes. c.1487T>C has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B, Montenegro_2022). 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 and showed that this variant resulted in decreased enzyme activity (Clark_2018). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 04, 2020 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 06, 2016 | - - |
Mucopolysaccharidosis, MPS-III-B;C5569050:Charcot-Marie-Tooth disease axonal type 2V Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 02, 2021 | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 496 of the NAGLU protein (p.Leu496Pro). This variant is present in population databases (rs569519789, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with NAGLU-related conditions. ClinVar contains an entry for this variant (Variation ID: 497482). 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. Experimental studies have shown that this missense change affects NAGLU function (PMID: 29979746). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at