VCV000003092.7 - ClinVar

NM_000487.6(ARSA):c.1229C>T (p.Thr410Ile)

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.

(3)

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.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000487.6(ARSA):c.1229C>T (p.Thr410Ile)

Variation ID: 3092 Accession: VCV000003092.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 22q13.33 22: 50625446 (GRCh38) [ NCBI UCSC ] 22: 51063874 (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 14, 2016	Jun 2, 2024	Nov 6, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000487.6:c.1229C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000478.3:p.Thr410Ile	missense
NM_000487.5:c.1229C>T
NM_001085425.3:c.1229C>T	NP_001078894.2:p.Thr410Ile	missense
NM_001085426.3:c.1229C>T	NP_001078895.2:p.Thr410Ile	missense
NM_001085427.3:c.1229C>T	NP_001078896.2:p.Thr410Ile	missense
NM_001085428.3:c.971C>T	NP_001078897.1:p.Thr324Ile	missense
NM_001362782.2:c.971C>T	NP_001349711.1:p.Thr324Ile	missense
NC_000022.11:g.50625446G>A
NC_000022.10:g.51063874G>A
NG_009260.2:g.7734C>T

... more HGVS ... less HGVS

Protein change

T410I, T324I

Other names

T408I

Canonical SPDI

NC_000022.11:50625445:G: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]

As described in PMID: 37480112, ARSA enzymatic activity of 2 to <4% of wild type is taken as moderate and likely 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 0.00000

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA116009 OMIM: 607574.0045 dbSNP: rs28940895 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, adult type	Pathogenic (1)	no assertion criteria provided	Jul 1, 2001	RCV000003238.3
Metachromatic leukodystrophy	Likely pathogenic (2)	criteria provided, single submitter	Nov 6, 2023	RCV001376978.6

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 (Nov 06, 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: SCV001574193.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 11456299‚ 28749476 Comment: This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 410 of the ARSA protein (p.Thr410Ile). … (more) This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 410 of the ARSA protein (p.Thr410Ile). This variant is present in population databases (rs28940895, gnomAD 0.002%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 11456299, 28749476). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as Thr408Ile. ClinVar contains an entry for this variant (Variation ID: 3092). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ARSA protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
Pathogenic (Jul 01, 2001)	no assertion criteria provided Method: literature only	METACHROMATIC LEUKODYSTROPHY, ADULT Affected status: not provided Allele origin: germline	OMIM Accession: SCV000023396.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 14, 2016	Publications: PubMed (1) PubMed: 11456299 Comment on evidence: Comabella et al. (2001) reported a consanguineous Spanish family in which a proband and her daughter had atypical adult-onset metachromatic leukodystrophy (250100) presenting as isolated … (more) Comabella et al. (2001) reported a consanguineous Spanish family in which a proband and her daughter had atypical adult-onset metachromatic leukodystrophy (250100) presenting as isolated peripheral neuropathy. Electrophysiologic studies were consistent with a chronic acquired demyelinating polyneuropathy. Both patients were compound heterozygotes for 2 mutations in the ARSA gene: a G-A transition at IVS2 (607574.0003) and a 1223C-T transition resulting in a thr408-to-ile (T408I) substitution. The mutations segregated independently; the unaffected father was a carrier for the IVS2 mutation and 2 daughters from the proband's second marriage were each carriers for 1 or the other of the mutations. Noting that homozygosity for the IVS2 mutation results in severe infantile disease, the authors concluded that the T408I mutation has a relatively mild effect. (less)
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: SCV005046758.1 First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024	Publications: PubMed (1) PubMed: 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: 2.91% of wild type enzymatic activity

Comment:

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 410 of the ARSA protein (p.Thr410Ile). This variant is present in population databases (rs28940895, gnomAD 0.002%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 11456299, 28749476). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as Thr408Ile. ClinVar contains an entry for this variant (Variation ID: 3092). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ARSA protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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)	tandem mass spectrometry used to measure enymatic activity Method citation(s): PubMed(1)	2.91% of wild type enzymatic activity	Gelb Laboratory, University of Washington Accession: SCV005046758.1	Publications PubMed (1) Comment: As described in PMID: 37480112, ARSA enzymatic activity of 2 to <4% of wild type is taken as moderate and likely 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
The wide genetic landscape of clinical frontotemporal dementia: systematic combined sequencing of 121 consecutive subjects.	Blauwendraat C	Genetics in medicine : official journal of the American College of Medical Genetics	2018	PMID: 28749476
Late-onset metachromatic leukodystrophy clinically presenting as isolated peripheral neuropathy: compound heterozygosity for the IVS2+1G-->A mutation and a newly identified missense mutation (Thr408Ile) in a Spanish family.	Comabella M	Annals of neurology	2001	PMID: 11456299

Text-mined citations for rs28940895 ...

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.1229C>T (p.Thr410Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs28940895 ...