VCV000093115.8 - ClinVar

NM_000487.6(ARSA):c.1108-2A>G

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.

(7)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000487.6(ARSA):c.1108-2A>G

Variation ID: 93115 Accession: VCV000093115.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 22q13.33 22: 50625683 (GRCh38) [ NCBI UCSC ] 22: 51064111 (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	Jun 28, 2015	Feb 4, 2024	Aug 17, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000487.6:c.1108-2A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_001085425.3:c.1108-2A>G		splice acceptor
NM_001085426.3:c.1108-2A>G		splice acceptor
NM_001085427.3:c.1108-2A>G		splice acceptor
NM_001085428.3:c.850-2A>G		splice acceptor
NM_001362782.2:c.850-2A>G		splice acceptor
NC_000022.11:g.50625683T>C
NC_000022.10:g.51064111T>C
NG_009260.2:g.7497A>G

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000022.11:50625682:T:C

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

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.

Links

ClinGen: CA278420 dbSNP: rs398123411 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.
Metachromatic leukodystrophy	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Aug 17, 2023	RCV000078932.9
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jul 9, 2015	RCV000482171.5

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.
Pathogenic (Nov 01, 2012)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000110792.8 First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ARSA Number of individuals with the variant: 7 Sex: mixed
Pathogenic (Dec 07, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Metachromatic leukodystrophy Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001520710.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
pathogenic (Aug 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Metachromatic leukodystrophy Affected status: yes Allele origin: germline	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn Accession: SCV004239256.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Pathogenic (Jan 23, 2018)	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: SCV000797335.1 First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015	Publications: PubMed (2) PubMed: 26462614‚ 24001781
Pathogenic (Jul 09, 2015)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000567088.4 First in ClinVar: Apr 27, 2017 Last updated: Dec 15, 2018	Comment: The c.1108-2A>G variant in the ARSA gene has been reported previously (reported as c.1102-2A>G due to alternative nomenclature) in the homozygous state in association with … (more) The c.1108-2A>G variant in the ARSA gene has been reported previously (reported as c.1102-2A>G due to alternative nomenclature) in the homozygous state in association with metachromatic leukodystrophy in an 11-year-old (Luzi et al., 2013). This splice site substitution destroys the canonical splice acceptor site in intron 6. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.1108-2A>G variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.1108-2A>G as a pathogenic variant. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Metachromatic leukodystrophy Affected status: yes Allele origin: germline	Pathology and Clinical Laboratory Medicine, King Fahad Medical City Accession: SCV002073809.1 First in ClinVar: Feb 09, 2022 Last updated: Feb 09, 2022	Number of individuals with the variant: 8 Ethnicity/Population group: Arab Geographic origin: Middle East
Pathogenic (Nov 12, 2020)	no assertion criteria provided Method: clinical testing	Metachromatic leukodystrophy Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV001469149.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021

Comment:

The c.1108-2A>G variant in the ARSA gene has been reported previously (reported as c.1102-2A>G due to alternative nomenclature) in the homozygous state in association with metachromatic leukodystrophy in an 11-year-old (Luzi et al., 2013). This splice site substitution destroys the canonical splice acceptor site in intron 6. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.1108-2A>G variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.1108-2A>G as a pathogenic variant.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mutation Update of ARSA and PSAP Genes Causing Metachromatic Leukodystrophy.	Cesani M	Human mutation	2016	PMID: 26462614
Sixteen novel mutations in the arylsulfatase A gene causing metachromatic leukodystrophy.	Luzi P	Gene	2013	PMID: 24001781
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ARSA	-	-	-	-

Text-mined citations for rs398123411 ...

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 Feb 14, 2024

ClinVar Genomic variation as it relates to human health

NM_000487.6(ARSA):c.1108-2A>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs398123411 ...