22-50626234-A-G
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000487.6(ARSA):c.899T>C(p.Leu300Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,252 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 (★★).
Frequency
Consequence
NM_000487.6 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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ARSA | NM_000487.6 | c.899T>C | p.Leu300Ser | missense_variant | Exon 5 of 8 | ENST00000216124.10 | NP_000478.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ARSA | ENST00000216124.10 | c.899T>C | p.Leu300Ser | missense_variant | Exon 5 of 8 | 1 | NM_000487.6 | ENSP00000216124.5 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461252Hom.: 0 Cov.: 35 AF XY: 0.00000550 AC XY: 4AN XY: 726908
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
Metachromatic leukodystrophy Pathogenic:2
Variant summary: ARSA c.899T>C (p.Leu300Ser), also reported as "L298S" and "L289S" [typo in publication], 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 was absent in 248700 control chromosomes. c.899T>C has been reported in the presumed compound heterozygous state in the literature in multiple individuals affected with Metachromatic Leukodystrophy (example, Kurosawa_1998, Lee_2019, Santhanakumaran_2022, Cesani_2016). These data indicate that the variant is 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, Kurosawa_1998). The following publications have been ascertained in the context of this evaluation (PMID: 9819708, 31312839, 36240581, 19154224). ClinVar contains an entry for this variant (Variation ID: 68157). Based on the evidence outlined above, the variant was classified as pathogenic. -
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 sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 300 of the ARSA protein (p.Leu300Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with metachromatic leukodystrophy (PMID: 9819708, 31312839). This variant is also known as L298S. ClinVar contains an entry for this variant (Variation ID: 68157). Experimental studies have shown that this missense change affects ARSA function (PMID: 9819708, 31312839). 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. -
not provided Pathogenic:1Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at