chr22-50626877-G-A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong
The NM_000487.6(ARSA):c.641C>T(p.Ala214Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000874 in 1,613,354 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A214T) 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 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARSA | NM_000487.6 | c.641C>T | p.Ala214Val | missense_variant | 3/8 | ENST00000216124.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARSA | ENST00000216124.10 | c.641C>T | p.Ala214Val | missense_variant | 3/8 | 1 | NM_000487.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152192Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 250702Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135692
GnomAD4 exome AF: 0.0000910 AC: 133AN: 1461162Hom.: 0 Cov.: 33 AF XY: 0.0000963 AC XY: 70AN XY: 726866
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152192Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74348
ClinVar
Submissions by phenotype
Metachromatic leukodystrophy Pathogenic:5Other:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1993 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 214 of the ARSA protein (p.Ala214Val). This variant is present in population databases (rs74315467, gnomAD 0.004%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 7906588, 9090526, 9192271, 14517960, 26462614). This variant is also known as p.Ala212Val. ClinVar contains an entry for this variant (Variation ID: 3070). 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: 9192271). 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 | Sep 07, 2019 | Variant summary: ARSA c.641C>T (p.Ala214Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250702 control chromosomes. c.641C>T has been reported in the literature in multiple individuals affected with Metachromatic Leukodystrophy (Barth_1993, Gort_1999, Eng_2003, Luzi_2013, Cesani_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
not provided, no classification provided | in vitro | Gelb Laboratory, University of Washington | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 18, 2016 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 13, 2014 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at