rs74315470

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000487.6(ARSA):c.736C>T(p.Arg246Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000026 in 1,613,986 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. R246H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

ARSA
NM_000487.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 6.07

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 18 ACMG points.

PM1

In a helix (size 22) in uniprot entity ARSA_HUMAN there are 18 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 chr22-50626708-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.97

PP5

Variant 22-50626709-G-A is Pathogenic according to our data. Variant chr22-50626709-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50626709-G-A is described in Lovd as [Pathogenic]. Variant chr22-50626709-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSA	NM_000487.6 link	c.736C>T	p.Arg246Cys	missense_variant	4/8	ENST00000216124.10	NP_000478.3	P15289A0A0C4DFZ2B4DVI5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARSA	ENST00000216124.10 link	c.736C>T	p.Arg246Cys	missense_variant	4/8	1	NM_000487.6	ENSP00000216124.5		A0A0C4DFZ2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

251026

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135794

show subpopulations

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000280

AC:

AN:

1461766

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727182

show subpopulations

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:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000342

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Metachromatic leukodystrophy

Pathogenic:6Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.736C>T (p.Arg246Cys) in ARSA gene has been observed in individuals affected with metachromatic leukodystrophy (Luzi P et.al.,2013). This variant has been reported to the ClinVar database as Pathogenic. The p.Arg246Cys variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.0007967% is reported in gnomAD. The amino acid Arg at position 246 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg246Cys in ARSA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic . -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jun 19, 2014	- -
not provided, no classification provided	in vitro	Gelb Laboratory, University of Washington	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 07, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 23, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 246 of the ARSA protein (p.Arg246Cys). This variant is present in population databases (rs74315470, gnomAD 0.002%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 22993277, 24001781, 26462614, 28670130). This variant is also known as p.Arg244Cys. ClinVar contains an entry for this variant (Variation ID: 3073). 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%. This variant disrupts the p.Arg246 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9090526, 22993277, 25965562, 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 29, 2019	- -

Metachromatic leukodystrophy, juvenile type

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Dec 23, 2022

This sequence change in ARSA is predicted to replace arginine with cysteine at codon 246, p.(Arg246Cys) (historically described as c.730C>T p.Arg244Cys). The arginine residue is highly conserved (94/94 vertebrates, UCSC), and is located in the sulfatase domain. There is a large physicochemical difference between arginine and cysteine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.002% (2/113,422 alleles) in the European (non-Finnish) population, which is consistent with a recessive disease. This variant has been detected in the homozygous and compound heterozygous state with a second pathogenic allele in multiple individuals with arylsulfatase A (ASA) deficiency. The phenotype was mainly late-infantile or juvenile metachromatic leukodystrophy (PMID: 9090526, 16966551, 19815439, 22993277, 26462614, 36240581). At least one patient with this variant displayed very low ASA activity in leukocytes and abnormally high sulfatide excretion in urine, which is highly specific for ASA deficiency (PMID: 22993277). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/5 algorithms). Another missense variant (c.737G>A p.Arg246His) in the same codon with a smaller physicochemical difference has been classified as likely pathogenic for ASA deficiency (PMID: 26462614, 9090526, 22993277, 25965562). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM5, PP3, PP4. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.50

D;D;D;.;D

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

.;.;.;D;D

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.97

D;D;D;D;D

MetaSVM

Pathogenic

1.1

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-6.4

D;D;D;D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0020

D;D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D;D

Vest4

0.94

MVP

0.83

ClinPred

0.99

GERP RS

5.4

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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