17-42536615-C-T
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM5PP3_ModeratePP5_Very_Strong
The NM_000263.4(NAGLU):c.343C>T(p.Pro115Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000969 in 1,342,270 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P115L) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000263.4 missense
Scores
Clinical Significance
Conservation
Publications
- mucopolysaccharidosis type 3BInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet, Myriad Women’s Health
- Charcot-Marie-Tooth disease axonal type 2VInheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
Genome browser will be placed here
ACMG classification
Our verdict: Pathogenic. The variant received 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NAGLU | NM_000263.4 | c.343C>T | p.Pro115Ser | missense_variant | Exon 1 of 6 | ENST00000225927.7 | NP_000254.2 | |
NAGLU | XM_024450771.2 | c.343C>T | p.Pro115Ser | missense_variant | Exon 1 of 7 | XP_024306539.1 | ||
NAGLU | XM_047436138.1 | c.-119C>T | 5_prime_UTR_variant | Exon 1 of 5 | XP_047292094.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NAGLU | ENST00000225927.7 | c.343C>T | p.Pro115Ser | missense_variant | Exon 1 of 6 | 1 | NM_000263.4 | ENSP00000225927.1 | ||
NAGLU | ENST00000586516.5 | c.92C>T | p.Ala31Val | missense_variant | Exon 1 of 4 | 2 | ENSP00000467135.1 | |||
NAGLU | ENST00000591587.1 | c.86C>T | p.Ala29Val | missense_variant | Exon 1 of 4 | 5 | ENSP00000467836.1 | |||
ENSG00000266929 | ENST00000585572.1 | n.106C>T | non_coding_transcript_exon_variant | Exon 1 of 5 | 4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD2 exomes AF: 0.0000110 AC: 1AN: 91056 AF XY: 0.0000193 show subpopulations
GnomAD4 exome AF: 0.00000969 AC: 13AN: 1342270Hom.: 0 Cov.: 30 AF XY: 0.0000106 AC XY: 7AN XY: 661966 show subpopulations
Age Distribution
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Mucopolysaccharidosis, MPS-III-B;C5569050:Charcot-Marie-Tooth disease axonal type 2V Pathogenic:2
- -
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 115 of the NAGLU protein (p.Pro115Ser). 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: 9443878, 27590925). ClinVar contains an entry for this variant (Variation ID: 553505). 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. -
Mucopolysaccharidosis, MPS-III-B Pathogenic:1
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
not provided Pathogenic:1
Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 29979746); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24314109, 9443878, 27590925, 19516195, 29661560, 26075876, 9832037, 11668611, 29979746) -
Intellectual disability Benign:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at