rs199476370
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP5BP4
The NM_000487.6(ARSA):c.1156C>T(p.Arg386Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R386H) has been classified as Uncertain significance.
Frequency
Consequence
NM_000487.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARSA | NM_000487.6 | c.1156C>T | p.Arg386Cys | missense_variant | 7/8 | ENST00000216124.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARSA | ENST00000216124.10 | c.1156C>T | p.Arg386Cys | missense_variant | 7/8 | 1 | NM_000487.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152164Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251092Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135864
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461500Hom.: 0 Cov.: 46 AF XY: 0.0000165 AC XY: 12AN XY: 727036
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152164Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74344
ClinVar
Submissions by phenotype
Metachromatic leukodystrophy Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 05, 2020 | This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Sep 20, 2021 | This variant was identified as compound heterozygous with NM_000487.6:c.449C>T. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 386 of the ARSA protein (p.Arg386Cys). This variant is present in population databases (rs199476370, gnomAD 0.005%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 9090526, 28762252; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Arg384Cys. ClinVar contains an entry for this variant (Variation ID: 68115). 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 ARSA protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 29, 2024 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 06, 2023 | Variant summary: ARSA c.1156C>T (p.Arg386Cys) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251092 control chromosomes (gnomAD). c.1156C>T has been reported in the literature in individuals affected with Metachromatic Leukodystrophy (examples: Draghia_1997 and Bohringer_2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28762252, 9090526). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
not provided Other:1
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at