16-88841077-T-A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong
The NM_000512.5(GALNS):c.337A>T(p.Ile113Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,612,652 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I113T) 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 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GALNS | NM_000512.5 | c.337A>T | p.Ile113Phe | missense_variant | 4/14 | ENST00000268695.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GALNS | ENST00000268695.10 | c.337A>T | p.Ile113Phe | missense_variant | 4/14 | 1 | NM_000512.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000790 AC: 12AN: 151808Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000399 AC: 10AN: 250884Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135850
GnomAD4 exome AF: 0.000151 AC: 220AN: 1460844Hom.: 0 Cov.: 31 AF XY: 0.000157 AC XY: 114AN XY: 726742
GnomAD4 genome AF: 0.0000790 AC: 12AN: 151808Hom.: 0 Cov.: 33 AF XY: 0.0000540 AC XY: 4AN XY: 74136
ClinVar
Submissions by phenotype
Mucopolysaccharidosis, MPS-IV-A Pathogenic:5Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 113 of the GALNS protein (p.Ile113Phe). This variant is present in population databases (rs118204438, gnomAD 0.009%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 7668283, 25137622; Invitae). ClinVar contains an entry for this variant (Variation ID: 703). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GALNS protein function. Experimental studies have shown that this missense change affects GALNS function (PMID: 7668283). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
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 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) - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The GALNS c.337A>T (p.Ile113Phe) missense variant is described as the second most frequently reported pathogenic variant, accounting for five percent of mucopolysaccharidosis type IV type A patient alleles (Morrone et al. 2014), and is especially common among patients of British and Irish descent. Across a selection of the available literature, the p.Ile113Phe variant has been identified in a homozygous state in two patients with mucopolysaccharidosis type IV, in a compound heterozygous state in 11 patients, and in a heterozygous state in six patients (Tomatsu et al. 1995; Yamada et al. 1998; Tomatsu et al. 2004; Dung et al. 2013; Bhattacharya et al. 2014). The p.Ile113Phe variant was absent from 300 control chromosomes (Tomatsu et al. 1995; Yamada et al. 1998; Tomatsu et al. 2004) and is reported at a frequency of 0.00012 in the European American population of the Exome Sequencing Project; however, this frequency is based on one allele only in a region of good sequence coverage, suggesting the variant is rare. In vitro transient expression studies showed that the p.Ile113Phe variant reduced cDNA expression to approximately five percent of wild type (Tomatsu et al. 1995; Sukegawa et al. 2000). Based on the collective evidence, the p.Ile113Phe variant is classified as pathogenic for mucopolysaccharidosis type IV. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1998 | - - |
Morquio syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 03, 2019 | Variant summary: GALNS c.337A>T (p.Ile113Phe) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 250984 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in GALNS causing Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (4e-05 vs 0.002), allowing no conclusion about variant significance. c.337A>T has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (Yamada_1998, Tomatsu_2004, Dung_2013). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating the effects of the variant on protein function. The most pronounced variant effect results in <10% of normal activity (Yamada_1998, Sukegawa_2000). Two ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 22, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at