VCV000093124.23 - ClinVar

NM_000487.6(ARSA):c.583del (p.Trp195fs)

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.

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.583del (p.Trp195fs)

Variation ID: 93124 Accession: VCV000093124.23

Type and length

Deletion, 1 bp

Location

Cytogenetic: 22q13.33 22: 50626935 (GRCh38) [ NCBI UCSC ] 22: 51065363 (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	Oct 20, 2024	Dec 21, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000487.6:c.583del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000478.3:p.Trp195fs	frameshift
NM_000487.6:c.583delT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000487.5:c.583del
NM_001085425.3:c.583del	NP_001078894.2:p.Trp195fs	frameshift
NM_001085426.3:c.583del	NP_001078895.2:p.Trp195fs	frameshift
NM_001085427.3:c.583del	NP_001078896.2:p.Trp195fs	frameshift
NM_001085428.3:c.325del	NP_001078897.1:p.Trp109fs	frameshift
NM_001362782.2:c.325del	NP_001349711.1:p.Trp109fs	frameshift
NC_000022.11:g.50626935del
NC_000022.10:g.51065363del
NG_009260.2:g.6245del

... more HGVS ... less HGVS

Protein change

W109fs, W195fs

Other names

Canonical SPDI

NC_000022.11:50626934:A:

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]

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Links

ClinGen: CA278424 dbSNP: rs398123416 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	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 1, 2023	RCV000078948.19
Metachromatic leukodystrophy	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Dec 21, 2023	RCV001251199.8

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 (Mar 27, 2013)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000110809.8 First in ClinVar: Jan 17, 2014 Last updated: Jun 28, 2015	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: 1 Sex: mixed
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Metachromatic leukodystrophy Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV001426592.1 First in ClinVar: Aug 09, 2020 Last updated: Aug 09, 2020	Publications: PubMed (1) PubMed: 32860008
Pathogenic (May 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004011420.12 First in ClinVar: Jul 16, 2023 Last updated: Oct 20, 2024	Comment: ARSA: PVS1, PM3:Strong, PM2, PP4 Number of individuals with the variant: 1
Pathogenic (Dec 21, 2023)	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: SCV001592676.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 8962139‚ 10477432‚ 26462614 Comment: This sequence change creates a premature translational stop signal (p.Trp195Glyfs5) in the ARSA gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Trp195Glyfs5) in the ARSA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ARSA are known to be pathogenic (PMID: 8962139, 10477432). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with metachromatic leukodystrophy (PMID: 26462614). ClinVar contains an entry for this variant (Variation ID: 93124). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (-)	no assertion criteria provided Method: research	Metachromatic leukodystrophy (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Gene Mapping Laboratory, Hacettepe University Accession: SCV001441275.1 First in ClinVar: Jan 30, 2021 Last updated: Jan 30, 2021	Publications: PubMed (1) PubMed: 33335837 Comment: Clinical features, enzyme activities and urinary sulfatide levels are compatible with metachromatic leukodystrophy

Comment:

This sequence change creates a premature translational stop signal (p.Trp195Glyfs*5) in the ARSA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ARSA are known to be pathogenic (PMID: 8962139, 10477432). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with metachromatic leukodystrophy (PMID: 26462614). ClinVar contains an entry for this variant (Variation ID: 93124). For these reasons, this variant has been classified as Pathogenic.

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)	Method not provided	Result not provided	Gene Mapping Laboratory, Hacettepe University Accession: SCV001441275.1	Publications PubMed (1)

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort.	Bertoli-Avella AM	European journal of human genetics : EJHG	2021	PMID: 32860008
Comprehensive clinical, biochemical, radiological and genetic analysis of 28 Turkish cases with suspected metachromatic leukodystrophy and their relatives.	Pekgül F	Molecular genetics and metabolism reports	2020	PMID: 33335837
Mutation Update of ARSA and PSAP Genes Causing Metachromatic Leukodystrophy.	Cesani M	Human mutation	2016	PMID: 26462614
Identification of 12 novel mutations and two new polymorphisms in the arylsulfatase A gene: haplotype and genotype-phenotype correlation studies in Spanish metachromatic leukodystrophy patients.	Gort L	Human mutation	1999	PMID: 10477432
Phenotype of arylsulfatase A-deficient mice: relationship to human metachromatic leukodystrophy.	Hess B	Proceedings of the National Academy of Sciences of the United States of America	1996	PMID: 8962139
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ARSA	-	-	-	-

Text-mined citations for rs398123416 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000487.6(ARSA):c.583del (p.Trp195fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs398123416 ...