chr22-50626618-G-A

Position:

chr22-50626618-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000487.6(ARSA):c.827C>T(p.Thr276Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,786 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 (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ARSA
NM_000487.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 6.58

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:

ARSA (HGNC:):

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 8) in uniprot entity ARSA_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000487.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.942

PP5

Variant 22-50626618-G-A is Pathogenic according to our data. Variant chr22-50626618-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50626618-G-A is described in Lovd as [Pathogenic]. Variant chr22-50626618-G-A is described in Lovd as [Pathogenic]. Variant chr22-50626618-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSA	NM_000487.6 linkuse as main transcript	c.827C>T	p.Thr276Met	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 linkuse as main transcript	c.827C>T	p.Thr276Met	missense_variant	4/8	1	NM_000487.6	ENSP00000216124.5		A0A0C4DFZ2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461540

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727084

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Metachromatic leukodystrophy

Pathogenic:8Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 25, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 24, 2023	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 276 of the ARSA protein (p.Thr276Met). This variant is present in population databases (rs74315472, gnomAD no frequency). This missense change has been observed in individuals with metachromatic leukodystrophy (MLD) (PMID: 8104633, 18786133, 19815439, 26462614; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as T274M. ClinVar contains an entry for this variant (Variation ID: 3075). 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: 7825603, 8723680). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The homozygous p.Thr276Met variant (sometimes called p.Thr274Met) in ARSA was identified by our study in one individual with Metachromatic Leukodystrophy. The p.Thr276Met variant in ARSA has been reported in 18 individuals with metachromatic leukodystrophy (most of whom were Arabian or Lebanese), segregated with disease in 4 affected relatives from 2 families (PMID: 19815439, 26462614, 8104633, 7825603), and has been identified in 0.0004068% (1/245818) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs74315472). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported pathogenic and likely pathogenic by Invitae and others in ClinVar (Variation ID: 3075). Invitae also reported the presence of this variant in the compound heterozygous state and in an individual with metachromatic leukodystrophy, slightly increasing the likelihood that the p.Thr276Met variant is pathogenic. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that the p.Thr276Met variant may impact protein function by reducing or eliminating catalytic enzyme activity (PMID: 7825603, 8723680). However, these types of assays may not accurately represent biological function. In summary, the p.Thr276Met variant is pathogenic based off of our findings, multiple reports in ClinVar, and the literature. ACMG/AMP Criteria applied: PM2, PS3, PP1_Moderate, PP3, PM3_Supporting (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jul 20, 2014	- -
not provided, no classification provided	in vitro	Gelb Laboratory, University of Washington	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 23, 2017	Variant summary: The ARSA c.827C>T (p.Thr276Met) variant causes a missense change involving the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant is found in the Alkaline-phosphatase-like, core domain (IPR017850). The variant of interest has been observed in a large, broad control population, ExAC, in 1/119904 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic ARSA variant (0.0027951). Multiple studies showed this variant as co-segregating with MLD in families of Lebanese and Italian origins (Harvey_1993, Bertelli_2005). In addition, low arylsulfatase A and sulfatidase activity was observed in peripheral leukocytes and cultured skin fibroblasts in patients carrying the variant. Also, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 10, 2020	- -

ARSA-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 07, 2023

The ARSA c.827C>T variant is predicted to result in the amino acid substitution p.Thr276Met. In the literature this variant is also referred to as c.821C>T (p.Thr274Met). This variant has been reported in the compound heterozygous and homozygous states in individuals with late infantile metachromatic leukodystrophy (MLD) (Harvey et al. 1993. PubMed ID: 8104633; Family 3, Proband 4, Bertelli et al. 2006. PubMed ID: 16678723; Sample U7, Tan et al. 2009. PubMed ID: 19815439). This variant also led to decreased ARSA activity in the patients (Harvey et al. 1993. PubMed ID: 8104633; Bertelli et al. 2006. PubMed ID: 16678723; Tan et al. 2009. PubMed ID: 19815439). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 18, 2019

Not found in the total gnomAD dataset, and the data is high quality (0/279214 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. Very strong co-segregation with disease, and data include affected and unaffected individuals from multiple families. -

METACHROMATIC LEUKODYSTROPHY, SEVERE

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1993

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.66

D;D;D;.;D

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.92

.;.;.;D;D

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.94

D;D;D;D;D

MetaSVM

Pathogenic

1.0

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-5.9

D;D;D;D;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Vest4

0.76

MVP

0.98

ClinPred

1.0

GERP RS

5.3

gMVP

0.98

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