NM_000487.6(ARSA):c.1115G>A (p.Arg372Gln) AND Metachromatic leukodystrophy

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Jan 11, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000544790.22

Allele description [Variation Report for NM_000487.6(ARSA):c.1115G>A (p.Arg372Gln)]

NM_000487.6(ARSA):c.1115G>A (p.Arg372Gln)

Gene:

ARSA:arylsulfatase A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

22q13.33

Genomic location:

Preferred name:

NM_000487.6(ARSA):c.1115G>A (p.Arg372Gln)

Other names:

R370Q

HGVS:

NC_000022.11:g.50625674C>T
NG_009260.2:g.7506G>A
NM_000487.6:c.1115G>AMANE SELECT
NM_001085425.3:c.1115G>A
NM_001085426.3:c.1115G>A
NM_001085427.3:c.1115G>A
NM_001085428.3:c.857G>A
NM_001362782.2:c.857G>A
NP_000478.3:p.Arg372Gln
NP_001078894.2:p.Arg372Gln
NP_001078895.2:p.Arg372Gln
NP_001078896.2:p.Arg372Gln
NP_001078897.1:p.Arg286Gln
NP_001349711.1:p.Arg286Gln
NC_000022.10:g.51064102C>T
NM_000487.5:c.1115G>A

Protein change:

R286Q; ARG370GLN

Links:

OMIM: 607574.0034; dbSNP: rs74315477

NCBI 1000 Genomes Browser:

rs74315477

Molecular consequence:

NM_000487.6:c.1115G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001085425.3:c.1115G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001085426.3:c.1115G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001085427.3:c.1115G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001085428.3:c.857G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001362782.2:c.857G>A - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

functionally_normal [Sequence Ontology: SO:0002219] - Comment(s)

Condition(s)

Name:: Metachromatic leukodystrophy (MLD)
Synonyms:: Metachromatic leukoencephalopathy; Sulfatide lipidosis; Cerebral sclerosis diffuse metachromatic form; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0018868; MedGen: C0023522; Orphanet: 512; OMIM: 250100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000627135	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 11, 2024)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 7866401, 28762252, 31694723, 32617873, 7825603, 12086582, 16678723, 18786133, 33385934, 28492532
SCV001781530	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002051336	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 14, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 7866401, 31694723, 28762252, 12086582, 32617873, 36240581 Citation Link,
SCV002060279	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Likely pathogenic (Nov 11, 2021)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15720392, 32617873, 28762252, 31694723, 12086582 Citation Link,
SCV002557353	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 24, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16678723, 31694723, 33855715, 25741868
SCV003811078	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 30, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005046790	Gelb Laboratory, University of Washington	no classification provided	not provided	not applicable	in vitro	PubMed (4) [See all records that cite these PMIDs] 32632536, 9452102, 31694723, 37480112

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	in vitro
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Multiple mutations are responsible for the high frequency of metachromatic leukodystrophy in a small geographic area.

Heinisch U, Zlotogora J, Kafert S, Gieselmann V.

Am J Hum Genet. 1995 Jan;56(1):51-7.

PubMed [citation]

PMID:: 7825603
PMCID:: PMC1801341

Metachromatic leukodystrophy - mutation analysis provides further evidence of genotype-phenotype correlation.

Biffi A, Cesani M, Fumagalli F, Del Carro U, Baldoli C, Canale S, Gerevini S, Amadio S, Falautano M, Rovelli A, Comi G, Roncarolo MG, Sessa M.

Clin Genet. 2008 Oct;74(4):349-57. doi: 10.1111/j.1399-0004.2008.01058.x. Epub 2008 Sep 11.

PubMed [citation]

PMID:: 18786133

See all PubMed Citations (17)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000627135.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India, SCV001781530.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002051336.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV002060279.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002557353.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003811078.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Gelb Laboratory, University of Washington, SCV005046790.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	in vitro	PubMed (4)

Description

"0 to < 2% of wild type ARSA enzymatic activity is taken as severe, 2 to <4% is taken moderate, 4 to 13% is taken as mild, and >13% is taken as benign, see PMID: 37480112"

PubMed [ID: 37480112]

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	not applicable	not applicable	not provided	not provided	assert pathogenicity		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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