rs199476349

Positions:

• chr22-50626250-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000216124.10(ARSA):​c.883G>A​(p.Gly295Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,182 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. G295C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ARSA ENST00000216124.10 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 O:2
• Conservation: PhyloP100: 6.05

Genes affected

ARSA (HGNC:713): (arylsulfatase A) The protein encoded by this gene hydrolyzes cerebroside sulfate to cerebroside and sulfate. Defects in this gene lead to metachromatic leucodystrophy (MLD), a progressive demyelination disease which results in a variety of neurological symptoms and ultimately death. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Dec 2010]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in ENST00000216124.10
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-50626249-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68155.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1, not_provided=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 22-50626250-C-T is Pathogenic according to our data. Variant chr22-50626250-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50626250-C-T is described in Lovd as [Pathogenic]. Variant chr22-50626250-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSA	NM_000487.6	c.883G>A	p.Gly295Ser	missense_variant	5/8	ENST00000216124.10	NP_000478.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARSA	ENST00000216124.10	c.883G>A	p.Gly295Ser	missense_variant	5/8	1	NM_000487.6	ENSP00000216124	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 248784 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 134948

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461182 Hom.: 0 Cov.: 35 AF XY: 0.00000825 AC XY: 6 AN XY: 726920

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metachromatic leukodystrophy Pathogenic:6 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 09, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The ARSA c.883G>A (p.Gly295Ser) variant (previously reported as c.887G>A, p.Gly293Ser) has been reported in two studies in which it was found in a compound heterozygous state with a second missense variant in a total of three individuals with metachromatic leukodystrophy (Berna et al. 2004; Biffi et al. 2008). One of the compound heterozygous individuals was also heterozygous for two additional variants (one known phenotype modifier and one functional polymorphism known to reduce enzyme activity) but did not carry the most common pseudodeficiency alleles (Biffi et al. 2008). Control data are unavailable for this variant, which is reported at a frequency of 0.00003 in the European (non-Finnish) population of the Exome Aggregation Consortium. However, this frequency is based on two alleles only in a region of good sequence coverage, suggesting the variant is rare. The p.Gly295Ser variant is located in a conserved residue in a functionally important domain of the protein. Functional studies in BHK-21 cells demonstrated the variant to be a null allele, causing the complete loss of enzyme activity (Berna et al. 2004). Based on the evidence, the p.Gly295Ser variant is classified as likely pathogenic for arylsulfatase A deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 11, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ARSA function (PMID: 15326627). 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: 68154). This variant is also known as Gly293Ser. This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 15326627, 18786133). This variant is present in population databases (rs199476349, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 295 of the ARSA protein (p.Gly295Ser). -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Oct 28, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 18, 2023	Variant summary: ARSA c.883G>A (p.Gly295Ser) 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 1.2e-05 in 248784 control chromosomes. c.883G>A has been reported in the literature in multiple compound heterozygous individuals affected with Metachromatic Leukodystrophy, including with adult and early juvenille onset (e.g. Berna_2004, Biffi_2008, Santhanakumaran_2022). 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 null enzyme activity in vitro (e.g. Berna_2004). The following publications have been ascertained in the context of this evaluation (PMID: 15326627, 18786133, 36240581). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=4) or likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 19, 2021	- -
not provided, no classification provided	in vitro	Gelb Laboratory, University of Washington	-	- -

not provided Pathogenic:3 Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 25, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2024	Published functional studies found G295S is associated with no detectable ARSA activity (PMID: 15326627); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Previously reported as G293S due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 33185815, 15326627, 31418856, 34302356, 34055681, 18786133) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;T;T;.;T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	.;.;.;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.8	D;D;D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;T;D
Vest4		0.98
MVP		0.99
ClinPred		0.99	D
GERP RS		5.2
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199476349; hg19: chr22-51064678; COSMIC: COSV99332363; COSMIC: COSV99332363;