rs199476355

Positions:

chr22-50626264-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000487.6(ARSA):c.869G>A(p.Arg290His) variant causes a missense change. The variant allele was found at a frequency of 0.00018 in 1,613,024 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. R290C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

ARSA
NM_000487.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11O:2

Conservation

PhyloP100: 4.98

Variant links:

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]

ARSA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a helix (size 5) in uniprot entity ARSA_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_000487.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-50626265-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.9

PP5

Variant 22-50626264-C-T is Pathogenic according to our data. Variant chr22-50626264-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50626264-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSA	NM_000487.6 linkuse as main transcript	c.869G>A	p.Arg290His	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 linkuse as main transcript	c.869G>A	p.Arg290His	missense_variant	5/8	1	NM_000487.6	ENSP00000216124	P1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000117

AC:

AN:

248178

Hom.:

AF XY:

0.000104

AC XY:

AN XY:

134724

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS exome

AF:

0.0000656

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000205

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000188

AC:

274

AN:

1460792

Hom.:

Cov.:

AF XY:

0.000180

AC XY:

131

AN XY:

726736

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.0000190

Gnomad4 NFE exome

AF:

0.000224

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000105

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000148

Hom.:

Bravo

AF:

0.0000907

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Metachromatic leukodystrophy

Pathogenic:8Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 11, 2020	The p.Arg290His variant in ARSA (also described as p.Arg288His in the literature) has been reported in the compound heterozygous state in at least 5 individuals with metachromatic leukodystrophy (Gort 1999 PMID: 10477432, Rafi 2003 PMID: 12809637, Yaghootfam 2004 PMID:15139291, Cesani 2016 PMID: 26462614), 4 of whom had another disease-causing variant on the other copy of the ARSA gene. In these 4 individuals, the variant occurred on the background (in cis) of a pseudodeficiency allele (Gort 1999 PMID: 10477432, Rafi 2003 PMID: 12809637). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 68153) and has been identified in 0.02% (23/112038) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies using both patient fibroblasts and cultured cells show that this variant reduces enzyme activity (~2%), supporting an impact on protein function (Gort 1999 PMID: 10477432, Yaghootfam 2004 PMID:15139291). Computational prediction tools and conservation analyses also support an impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive metachromatic leukodystrophy. ACMG/AMP Criteria applied: PM3_Very Strong, PS3_Moderate, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 290 of the ARSA protein (p.Arg290His). This variant is present in population databases (rs199476355, gnomAD 0.02%). This missense change has been observed in individuals with metachromatic leukodystrophy (PMID: 10477432, 12809637, 15139291, 26462614). This variant is also known as R288H. ClinVar contains an entry for this variant (Variation ID: 68153). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on ARSA function (PMID: 15139291). This variant disrupts the p.Arg290 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7866401, 16678723, 17560502, 19815439, 26462614). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	in vitro	Gelb Laboratory, University of Washington	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 09, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 13, 2023	Criteria applied: PM3_VSTR,PM5_STR,PS4_SUP,PM2_SUP,PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 31, 2019	Variant summary: ARSA c.869G>A (p.Arg290His) results in a non-conservative amino acid change located in the Sulfatase, N-terminal (IPT000917) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 248178 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ARSA causing Metachromatic Leukodystrophy (0.00012 vs 0.0028), allowing no conclusion about variant significance. c.869G>A has been reported in the literature in individuals affected with Metachromatic Leukodystrophy (example, Gort_1999, Rafi_2003, Yaghooftam_2004, Cesani_2015). 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 40% of normal activity in a heterologous experimental system (Yaghooftam_2004). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1)/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 06, 2020	NM_000487.5(ARSA):c.869G>A(R290H) is classified as likely pathogenic in the context of metachromatic leukodystrophy. Sources cited for classification include the following: PMID 26462614, 12809637, 15139291 and 10477432. Classification of NM_000487.5(ARSA):c.869G>A(R290H) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided

Pathogenic:1Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as p.R288H; This variant is associated with the following publications: (PMID: 26462614, 12809637, 15139291, 10477432, 31589614, 30609409, 37480112) -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 12, 2022

The c.869G>A (p.R290H) alteration is located in exon 5 (coding exon 5) of the ARSA gene. This alteration results from a G to A substitution at nucleotide position 869, causing the arginine (R) at amino acid position 290 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.01% (29/248178) total alleles studied. The highest observed frequency was 0.02% (23/112038) of European (non-Finnish) alleles. This alteration has been detected in the homozygous state and as compound heterozygous in trans with other pathogenic ARSA alterations in multiple unrelated individuals with metachromatic leukodystrophy with enzymatic activity levels are reduced to <5% in patient fibroblasts compared to healthy controls (Cesani, 2016; Yaghootfam, 2004; Rafi, 2003; Gort, 1999; Guo, 2020). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

ARSA-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 02, 2023

The ARSA c.869G>A variant is predicted to result in the amino acid substitution p.Arg290His. This variant has been reported in the compound heterozygous state in several individuals with metachromatic leukodystrophy (Reported as R288H in Gort et al. 1999. PubMed ID: 10477432; Rafi et al. 2003. PubMed ID: 12809637; Cesani et al. 2015. PubMed ID: 26462614). A different amino acid substitution at this same position (c.868C>A, Arg290Ser) has also been reported in patients with metachromatic leukodystrophy (Reported as R288S in Luzi et al. 2013. PubMed ID: 24001781). This variant is reported in 0.021% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.33

T;T;T;.;T

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

.;.;.;D;D

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.90

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-2.0

N;N;N;N;N

REVEL

Pathogenic

0.87

Sift

Benign

0.54

T;T;T;T;T

Sift4G

Benign

0.54

T;T;T;T;T

Vest4

0.84

MVP

1.0

ClinPred

0.51

GERP RS

5.2

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over