rs121918172
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The ENST00000304895.9(GUSB):c.1856C>T(p.Ala619Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,612,926 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A619A) has been classified as Likely benign.
Frequency
Consequence
ENST00000304895.9 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GUSB | NM_000181.4 | c.1856C>T | p.Ala619Val | missense_variant | 12/12 | ENST00000304895.9 | NP_000172.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GUSB | ENST00000304895.9 | c.1856C>T | p.Ala619Val | missense_variant | 12/12 | 1 | NM_000181.4 | ENSP00000302728 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000330 AC: 5AN: 151428Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251494Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135922
GnomAD4 exome AF: 0.0000253 AC: 37AN: 1461498Hom.: 0 Cov.: 37 AF XY: 0.0000193 AC XY: 14AN XY: 727038
GnomAD4 genome AF: 0.0000330 AC: 5AN: 151428Hom.: 0 Cov.: 31 AF XY: 0.0000406 AC XY: 3AN XY: 73856
ClinVar
Submissions by phenotype
Mucopolysaccharidosis type 7 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 07, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 619 of the GUSB protein (p.Ala619Val). This variant is present in population databases (rs121918172, gnomAD 0.006%). This missense change has been observed in individual(s) with mucopolysaccharidosis Type VII (PMID: 1779626, 2115490, 30653816). ClinVar contains an entry for this variant (Variation ID: 893). 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 not expected to disrupt GUSB protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GUSB function (PMID: 1702266, 1779626, 2115490, 7633414, 19224584). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1991 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 07, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 2115490, 7633414, 32079065, 28595941, 8411710, 1702266, 19224584, 23777470, 1779626, 9543069, 32857898, 30653816) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at