rs74315456
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_000487.6(ARSA):c.293C>T(p.Ser98Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000389 in 1,594,964 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. S98L) has been classified as Pathogenic.
Frequency
Consequence
NM_000487.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARSA | NM_000487.6 | c.293C>T | p.Ser98Phe | missense_variant | 2/8 | ENST00000216124.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARSA | ENST00000216124.10 | c.293C>T | p.Ser98Phe | missense_variant | 2/8 | 1 | NM_000487.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152218Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000336 AC: 7AN: 208510Hom.: 0 AF XY: 0.0000262 AC XY: 3AN XY: 114508
GnomAD4 exome AF: 0.0000395 AC: 57AN: 1442746Hom.: 0 Cov.: 33 AF XY: 0.0000391 AC XY: 28AN XY: 716384
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152218Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74354
ClinVar
Submissions by phenotype
not provided Pathogenic:8
Likely pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 14, 2019 | Published functional studies demonstrate loss of enzyme activity (Gieselmann et al., 1991); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 1678251, 12809637, 32632536, 7649558, 16546179) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 08, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2017 | - - |
Metachromatic leukodystrophy Pathogenic:5Other:2
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Dec 09, 2014 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 21, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 13, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 05, 2021 | Variant summary: ARSA c.293C>T (p.Ser98Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.4e-05 in 208510 control chromosomes. c.293C>T has been reported in the literature in multiple individuals affected with Metachromatic Leukodystrophy (example, Gieselmann_1991, Rafi_2003, van Rappard_2016, Beerepoot_2020). 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. The most pronounced variant effect results in <10% of normal activity in-vitro (example, Gieselmann_1991). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 13, 2024 | This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 98 of the ARSA protein (p.Ser98Phe). This variant is present in population databases (rs74315456, gnomAD 0.007%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 1678251, 12809637, 22993277, 23701968). This variant is also known as c.287C>T, p.Ser96Phe. ClinVar contains an entry for this variant (Variation ID: 3054). 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 ARSA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ARSA function (PMID: 1678251). For these reasons, this variant has been classified as Pathogenic. - |
not provided, no classification provided | in vitro | Gelb Laboratory, University of Washington | - | - - |
Metachromatic leukodystrophy, late infantile form Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1989 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at