VCV000188949.11 - ClinVar

NM_000487.6(ARSA):c.979+1G>A

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/Likely 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.979+1G>A

Variation ID: 188949 Accession: VCV000188949.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 22q13.33 22: 50626153 (GRCh38) [ NCBI UCSC ] 22: 51064581 (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	Mar 29, 2015	Feb 14, 2024	Oct 28, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000487.6:c.979+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001085425.3:c.979+1G>A		splice donor
NM_001085426.3:c.979+1G>A		splice donor
NM_001085427.3:c.979+1G>A		splice donor
NM_001085428.3:c.721+1G>A		splice donor
NM_001362782.2:c.721+1G>A		splice donor
NC_000022.11:g.50626153C>T
NC_000022.10:g.51064581C>T
NG_009260.2:g.7027G>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000022.11:50626152:C:T

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: CA278479 dbSNP: rs754722529 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/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Oct 28, 2023	RCV000169323.11
not provided	Pathogenic (1)	criteria provided, single submitter	Mar 13, 2023	RCV003151752.1

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.
Likely pathogenic (Aug 28, 2014)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: literature only	Metachromatic leukodystrophy (Autosomal recessive inheritance) Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000220656.2 First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022	Publications: PubMed (2) PubMed: 19815439‚ 14517960
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Metachromatic leukodystrophy (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV002054026.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022	Sex: male
Pathogenic (Mar 13, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV003840880.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Comment: Reported as c.973+1 G>A and seen with a second ARSA variant, phase unknown, in a patient with juvenile MLD in the published literature (Eng et … (more) Reported as c.973+1 G>A and seen with a second ARSA variant, phase unknown, in a patient with juvenile MLD in the published literature (Eng et al., 2003); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34554397, 34276053, 14517960) (less)
Pathogenic (Oct 28, 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: SCV002295965.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (6) PubMed: 16199547‚ 8962139‚ 10477432‚ 14517960‚ 34276053‚ 34554397 Comment: This sequence change affects a donor splice site in intron 5 of the ARSA gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more) This sequence change affects a donor splice site in intron 5 of the ARSA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ARSA are known to be pathogenic (PMID: 8962139, 10477432). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individuals with metachromatic leukodystrophy (PMID: 14517960, 34276053, 34554397). This variant is also known as c.973+1G>A. ClinVar contains an entry for this variant (Variation ID: 188949). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	Metachromatic leukodystrophy (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence, Accession: SCV001478468.1 First in ClinVar: Feb 10, 2021 Last updated: Feb 10, 2021

Comment:

Reported as c.973+1 G>A and seen with a second ARSA variant, phase unknown, in a patient with juvenile MLD in the published literature (Eng et al., 2003); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34554397, 34276053, 14517960)

Comment:

This sequence change affects a donor splice site in intron 5 of the ARSA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ARSA are known to be pathogenic (PMID: 8962139, 10477432). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individuals with metachromatic leukodystrophy (PMID: 14517960, 34276053, 34554397). This variant is also known as c.973+1G>A. ClinVar contains an entry for this variant (Variation ID: 188949). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

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
Analysis of the HEXA, HEXB, ARSA, and SMPD1 Genes in 68 Iranian Patients.	Abtahi R	Journal of molecular neuroscience : MN	2022	PMID: 34554397
Multilocus disease-causing genomic variations for Mendelian disorders: role of systematic phenotyping and implications on genetic counselling.	Narayanan DL	European journal of human genetics : EJHG	2021	PMID: 34276053
Biochemical profiling to predict disease severity in metachromatic leukodystrophy.	Tan MA	Molecular genetics and metabolism	2010	PMID: 19815439
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
Identification of nine novel arylsulfatase a (ARSA) gene mutations in patients with metachromatic leukodystrophy (MLD).	Eng B	Human mutation	2003	PMID: 14517960
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

Text-mined citations for rs754722529 ...

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.979+1G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs754722529 ...