rs199476392
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000487.6(ARSA):āc.1289T>Cā(p.Leu430Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,449,994 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L430F) 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 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARSA | NM_000487.6 | c.1289T>C | p.Leu430Pro | missense_variant | 8/8 | ENST00000216124.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARSA | ENST00000216124.10 | c.1289T>C | p.Leu430Pro | missense_variant | 8/8 | 1 | NM_000487.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000138 AC: 2AN: 1449994Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1AN XY: 719530
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Metachromatic leukodystrophy Pathogenic:1Uncertain:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 11, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 25, 2023 | For these reasons, this variant has been classified as Pathogenic. This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 430 of the ARSA protein (p.Leu430Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of metachromatic leukodystrophy (PMID: 9272717, 26462614; 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 p.L428P. ClinVar contains an entry for this variant (Variation ID: 68119). 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. - |
not provided, no classification provided | in vitro | Gelb Laboratory, University of Washington | - | - - |
not provided Pathogenic:1Other:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 01, 2022 | Reported previously in a patient with juvenile metachromatic leukodystrophy who harbored a second variant in the ARSA gene; phase unknown (Cesani et al., 2015); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.L428P; This variant is associated with the following publications: (PMID: 26462614, 18693274, 26659599, 27915290, 9272717) - |
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