rs118204446
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000512.5(GALNS):āc.935C>Gā(p.Thr312Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,790 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 (ā ā ). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T312A) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000512.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GALNS | NM_000512.5 | c.935C>G | p.Thr312Ser | missense_variant | 9/14 | ENST00000268695.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GALNS | ENST00000268695.10 | c.935C>G | p.Thr312Ser | missense_variant | 9/14 | 1 | NM_000512.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152102Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 250636Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135654
GnomAD4 exome AF: 0.0000342 AC: 50AN: 1461688Hom.: 0 Cov.: 32 AF XY: 0.0000330 AC XY: 24AN XY: 727136
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152102Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74292
ClinVar
Submissions by phenotype
Mucopolysaccharidosis, MPS-IV-A Pathogenic:4Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1998 | - - |
Likely pathogenic, criteria provided, single submitter | research | Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova | Feb 01, 2021 | In vivo and in vitro functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; low to null in vitro enzymatic activity; PS3_moderate); the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_strong); very low frequency in gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 312 of the GALNS protein (p.Thr312Ser). This variant is present in population databases (rs118204446, gnomAD 0.004%). This missense change has been observed in individuals with MPS IVA (PMID: 9521421, 15235041). ClinVar contains an entry for this variant (Variation ID: 713). 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 GALNS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GALNS function (PMID: 9521421, 10814710). For these reasons, this variant has been classified as Pathogenic. - |
Morquio syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 11, 2019 | Variant summary: GALNS c.935C>G (p.Thr312Ser) results in a conservative amino acid change located in the Sulfatase, N-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250636 control chromosomes (gnomAD). c.935C>G has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A)(Yamada_1998). Authors indicate the variant causes a mild phenotype. These data indicate that the variant is very likely to be associated with disease. Functional analysis performed by Yamada_1998 found the variant to produce 15% normal activity. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at