22-50625674-C-T

Position:

chr22-50625674-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.1115G>A(p.Arg372Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,613,304 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. R372W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

ARSA
NM_000487.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 7.16

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 strand (size 3) in uniprot entity ARSA_HUMAN there are 5 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 chr22-50625675-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.924

PP5

Variant 22-50625674-C-T is Pathogenic according to our data. Variant chr22-50625674-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50625674-C-T is described in Lovd as [Pathogenic]. Variant chr22-50625674-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.1115G>A	p.Arg372Gln	missense_variant	7/8	ENST00000216124.10	NP_000478.3	P15289A0A0C4DFZ2B4DVI5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARSA	ENST00000216124.10 linkuse as main transcript	c.1115G>A	p.Arg372Gln	missense_variant	7/8	1	NM_000487.6	ENSP00000216124.5		A0A0C4DFZ2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152126

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250200

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135724

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:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1461178

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726874

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74330

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000457

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Metachromatic leukodystrophy

Pathogenic:7Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 14, 2023	Variant summary: ARSA c.1115G>A (p.Arg372Gln) results in a 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 4e-06 in 250200 control chromosomes. A different amino acid change at the same position (c.1114C>T resulting in p.Arg372Trp) has been classified as pathogenic by our lab. c.1115G>A has been reported in the literature as a homozygous and compound heterozygous genotype in at-least four individuals with infantile or early juvenille form of Metachromatic Leukodystrophy (MLD) (example, Bohringer_2017, Gieselmann_1994, Schestag_2002, Wu_2021, Santhanakumaran_2022) and as a compound heterozygous genotype with a pseudodeficiency allele in at-least two adult individuals reportedly affected with MLD (example, Hettiarachchi_2019) . 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 approximately 24% of normal activity in vitro (example, Schestag_2002). The authors conclude that this variant affects a cleft held together by an intra-molecular salt bridge and retains some residual activity as the smaller glutamine residue still allows the cleft to close, yielding a less severely affected enzyme. The following publications have been ascertained in the context of this evaluation (PMID: 7866401, 31694723, 28762252, 12086582, 32617873, 36240581). Four clinical diagnostic laboratories and the OMIM database have submitted clinical-significance assessments for this variant to ClinVar after 2014 (Likely pathogenic, n=2; Pathogenic, n=3, including OMIM). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 20, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 11, 2021	NM_000487.5(ARSA):c.1115G>A(R372Q) is a missense variant classified as likely pathogenic in the context of metachromatic leukodystrophy. R372Q has been observed in cases with relevant disease (PMID: 31694723, 12086582, 32617873, 28762252). Functional assessments of this variant are available in the literature (PMID: 12086582, 15720392). R372Q has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, NM_000487.5(ARSA):c.1115G>A(R372Q) is a missense variant that has functional support for pathogenicity and has been observed more frequently in cases with the relevant disease 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	Revvity Omics, Revvity	May 30, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 372 of the ARSA protein (p.Arg372Gln). This variant is present in population databases (rs74315477, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of metachromatic leukodystrophy (PMID: 7866401, 12086582, 28762252, 31694723, 32617873). This variant is also known as p.Arg370Gln or p.R370Q. ClinVar contains an entry for this variant (Variation ID: 3082). 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: 12086582). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg372 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7825603, 12086582, 16678723, 18786133, 33385934). 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. -
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 arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 2 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes). (I) 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) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. p.(Arg372Trp), also known as p.(Arg370Trp) in older manuscripts, has been reported in at least two homozygote or compound heterozygote individuals with metachromatic leukodystrophy (PMIDs:16678723, 33855715). It is also classified as likely pathogenic/pathogenic by multiple diagnositc laboratories in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least five homozygote or compound heterozygote individuals with metachromatic leukodystrophy; and consistently classified as pathogenic by diagnostic laboratories in ClinVar (PMID: 31694723). This variant is also known as p.(Arg370Gln) in older manuscripts. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided, no classification provided	in vitro	Gelb Laboratory, University of Washington	-	- -

METACHROMATIC LEUKODYSTROPHY, MILD

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.40

T;T;T;.;T

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

.;.;.;D;D

M_CAP

Pathogenic

0.59

MetaRNN

Pathogenic

0.92

D;D;D;D;D

MetaSVM

Pathogenic

1.1

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.5

D;D;D;D;D

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Uncertain

0.012

D;D;D;D;D

Vest4

0.75

MVP

1.0

ClinPred

1.0

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.29

Position offset: -33

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