rs74315471
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000487.6(ARSA):c.739G>A(p.Gly247Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000235 in 1,614,008 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 (★★). Synonymous variant affecting the same amino acid position (i.e. G247G) has been classified as Likely benign.
Frequency
Consequence
NM_000487.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARSA | NM_000487.6 | c.739G>A | p.Gly247Arg | missense_variant | 4/8 | ENST00000216124.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARSA | ENST00000216124.10 | c.739G>A | p.Gly247Arg | missense_variant | 4/8 | 1 | NM_000487.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152232Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 251038Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135786
GnomAD4 exome AF: 0.0000246 AC: 36AN: 1461776Hom.: 0 Cov.: 33 AF XY: 0.0000275 AC XY: 20AN XY: 727186
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152232Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74376
ClinVar
Submissions by phenotype
Metachromatic leukodystrophy Pathogenic:7Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 01, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ARSA function (PMID: 8101083). 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. ClinVar contains an entry for this variant (Variation ID: 3074). This variant is also known as p.Gly245Arg. This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 8101083, 26553228, 31186049). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs74315471, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 247 of the ARSA protein (p.Gly247Arg). - |
Pathogenic, criteria provided, single submitter | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Mar 23, 2024 | A heterozygous missense variant in exon 4 of the ARSA gene that results in the amino acid substitution of Arginine for Glycine at codon 247 was detected. The observed variant c.739G>A has not been reported in the 1000 genomes and has a MAF of 0.0012% in the gnomAD database. The in silico prediction of the variant is damaging by MutationTaster2, SIFT, PolyPhen2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 01, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense c.739G>A (p.Gly247Arg) variant has been observed in individual(s) with metachromatic leukodystrophy (Liaw HR et al). Experimental studies have shown that this missense change affects ARSA function (Hasegawa Y et al). 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) indicates that this missense variant is expected to disrupt ARSA protein function. This variant is reported with the allele frequency (0.0012%) in the gnomad and novel in 1000 genome database. It has been submitted to ClinVar as Pathogenic. The amino acid Gly at position 247 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jun 24, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with metachromatic leukodystrophy (MIM#250100). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 3 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Gly247Glu) has been reported in a compound heterozygote individual with metachromatic leukodystrophy (PMID: 27779215). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least six homozygote or compound heterozygote individuals with metachromatic leukodystrophy; and consistently classified as pathogenic by diagnostic laboratories in ClinVar (PMIDs: 31186049, 21167507). This variant is also known as p.(Gly245Arg) in older manuscripts. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Sep 08, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Suma Genomics | - | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 29, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 10, 2023 | Published functional studies demonstrate G247R does not induce enzyme activity (Hasegawa et al., 1993); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(G245R) due to use of alternate nomenclature; This variant is associated with the following publications: (PMID: 26553228, 8101083, 21167507, 31186049, 36789546) - |
Metachromatic leukodystrophy, severe Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 1993 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at