rs74315480
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000487.6(ARSA):c.1174C>T(p.Arg392Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,580 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. R392Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000487.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARSA | NM_000487.6 | c.1174C>T | p.Arg392Trp | missense_variant | 7/8 | ENST00000216124.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARSA | ENST00000216124.10 | c.1174C>T | p.Arg392Trp | missense_variant | 7/8 | 1 | NM_000487.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251156Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135872
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461420Hom.: 0 Cov.: 45 AF XY: 0.0000193 AC XY: 14AN XY: 727006
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74328
ClinVar
Submissions by phenotype
Metachromatic leukodystrophy Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 22, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 392 of the ARSA protein (p.Arg392Trp). This variant is present in population databases (rs74315480, gnomAD 0.006%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 21167507, 26462614, 26553228). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg390Trp. ClinVar contains an entry for this variant (Variation ID: 3085). 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. This variant disrupts the p.Arg392 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9452102, 20339381, 26462614). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 21, 2023 | Variant summary: ARSA c.1174C>T (p.Arg392Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251156 control chromosomes (gnomAD). c.1174C>T (also known as c.1168C>T, p.R390W) has been reported in the literature in multiple individuals affected with Metachromatic Leukodystrophy (example: Shukula_2011, Liaw_2015, and Mahdieh_2021). 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 (example: Liaw_2015). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=4) and VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jan 23, 2015 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 07, 2018 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Uncertain:1
Uncertain significance, flagged submission | clinical testing | Eurofins Ntd Llc (ga) | May 23, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at