VCV000068122.6 - ClinVar

NM_000487.6(ARSA):c.1471T>G (p.Cys491Gly)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(5)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Pathogenic(1); Uncertain significance(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000487.6(ARSA):c.1471T>G (p.Cys491Gly)

Variation ID: 68122 Accession: VCV000068122.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 22q13.33 22: 50625204 (GRCh38) [ NCBI UCSC ] 22: 51063632 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 22, 2013	Jun 2, 2024	Aug 31, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000487.6:c.1471T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000478.3:p.Cys491Gly	missense
NM_001085425.3:c.1471T>G	NP_001078894.2:p.Cys491Gly	missense
NM_001085426.3:c.1471T>G	NP_001078895.2:p.Cys491Gly	missense
NM_001085427.3:c.1471T>G	NP_001078896.2:p.Cys491Gly	missense
NM_001085428.3:c.1213T>G	NP_001078897.1:p.Cys405Gly	missense
NM_001362782.2:c.1213T>G	NP_001349711.1:p.Cys405Gly	missense
NC_000022.11:g.50625204A>C
NC_000022.10:g.51063632A>C
NG_009260.2:g.7976T>G

... more HGVS ... less HGVS

Protein change

C491G, C405G

Other names

Canonical SPDI

NC_000022.11:50625203:A:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

loss_of_function_variant; Sequence Ontology [ SO:0002054]

As described in PMID: 37480112, ARSA enzymatic activity of 4 to <13% of wild type is taken as moderate and may contributes to disease. [submitted by Gelb Laboratory, University of Washington]

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00001

Exome Aggregation Consortium (ExAC) 0.00003

Links

ClinGen: CA219000 UniProtKB/Swiss-Prot: VAR_054211 dbSNP: rs199476388 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ARSA		-	-	GRCh38 GRCh37	1256	1424

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	not provided (1)	no classification provided	-	RCV000058952.1
Metachromatic leukodystrophy	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Aug 31, 2022	RCV000667096.6
not specified	Uncertain significance (1)	criteria provided, single submitter	Mar 29, 2022	RCV002222376.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Mar 29, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002500741.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (3) PubMed: 26462614‚ 33855715‚ 15026521 Comment: Variant summary: ARSA c.1471T>G (p.Cys491Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging … (more) Variant summary: ARSA c.1471T>G (p.Cys491Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-06 in 238822 control chromosomes (gnomAD and publication data). c.1471T>G has been reported in the literature in individuals affected with Metachromatic Leukodystrophy (Gallo_2004, Cesani_2015, Fumagalli_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
Pathogenic (Aug 31, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Metachromatic leukodystrophy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003444353.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 15026521 Comment: For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, … (more) For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 68122). This variant is also known as C489S. This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 15026521; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs199476388, gnomAD 0.002%). This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 491 of the ARSA protein (p.Cys491Gly). (less)
Uncertain significance (May 17, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Metachromatic leukodystrophy Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000791493.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (3) PubMed: 15026521‚ 23208745‚ 26462614
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: not provided	UniProtKB/Swiss-Prot Accession: SCV000090473.1 First in ClinVar: Oct 22, 2013 Last updated: Oct 22, 2013
not provided (-)	no classification provided Method: in vitro	Metachromatic leukodystrophy (Autosomal recessive inheritance) Affected status: not applicable Allele origin: not applicable	Gelb Laboratory, University of Washington Accession: SCV005046767.1 First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024	Publications: PubMed (3) PubMed: 15026521‚ 26462614‚ 37480112 Comment on evidence: 0 to < 2% of wild type ARSA enzymatic activity is taken as severe, 2 to <4% is taken moderate, 4 to 13% is taken … (more) 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 (less) Method: tandem mass spectrometry used to measure enymatic activity Result: 8.72% of wild type enzymatic activity

Comment:

Variant summary: ARSA c.1471T>G (p.Cys491Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-06 in 238822 control chromosomes (gnomAD and publication data). c.1471T>G has been reported in the literature in individuals affected with Metachromatic Leukodystrophy (Gallo_2004, Cesani_2015, Fumagalli_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

Comment:

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 68122). This variant is also known as C489S. This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 15026521; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs199476388, gnomAD 0.002%). This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 491 of the ARSA protein (p.Cys491Gly).

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
loss_of_function_variant (SO:0002054)	tandem mass spectrometry used to measure enymatic activity Method citation(s): PubMed(1)	8.72% of wild type enzymatic activity	Gelb Laboratory, University of Washington Accession: SCV005046767.1	Publications PubMed (3) Comment: As described in PMID: 37480112, ARSA enzymatic activity of 4 to <13% of wild type is taken as moderate and may contributes to disease.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix.	Trinidad M	Genome biology	2023	PMID: 37480112
Metachromatic leukodystrophy: A single-center longitudinal study of 45 patients.	Fumagalli F	Journal of inherited metabolic disease	2021	PMID: 33855715
Mutation Update of ARSA and PSAP Genes Causing Metachromatic Leukodystrophy.	Cesani M	Human mutation	2016	PMID: 26462614
Complete mapping of a cystine knot and nested disulfides of recombinant human arylsulfatase A by multi-enzyme digestion and LC-MS analysis using CID and ETD.	Ni W	Journal of the American Society for Mass Spectrometry	2013	PMID: 23208745
Late onset MLD with normal nerve conduction associated with two novel missense mutations in the ASA gene.	Gallo S	Journal of neurology, neurosurgery, and psychiatry	2004	PMID: 15026521

Text-mined citations for rs199476388 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000487.6(ARSA):c.1471T>G (p.Cys491Gly)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs199476388 ...