Variant summary: ARSA c.925G>A (p.Glu309Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246094 control chromosomes (gnomAD). c.925G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Metachromatic Leukodystrophy (e.g. Biffi_2008, Cesani_2015, Guo_2020, Santhanakumaran_2022). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function in vitro and found the variant effect results in <10% of normal activity, even when overexpressed (e.g. Cesani_2009, Bohringer_2017). The following publications have been ascertained in the context of this evaluation (PMID: 18786133, 19606494, 26462614, 32875726, 36240581, 28762252). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000487.6(ARSA):c.925G>A (p.Glu309Lys)
Germline
Classification
Help
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)
Help
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
7
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.925G>A (p.Glu309Lys)
Variation ID: 68162 Accession: VCV000068162.22
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 22q13.33 22: 50626208 (GRCh38) [ NCBI UCSC ] 22: 51064636 (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 Oct 20, 2024 Nov 1, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000487.6:c.925G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000478.3:p.Glu309Lys missense NM_001085425.3:c.925G>A NP_001078894.2:p.Glu309Lys missense NM_001085426.3:c.925G>A NP_001078895.2:p.Glu309Lys missense NM_001085427.3:c.925G>A NP_001078896.2:p.Glu309Lys missense NM_001085428.3:c.667G>A NP_001078897.1:p.Glu223Lys missense NM_001362782.2:c.667G>A NP_001349711.1:p.Glu223Lys missense NC_000022.11:g.50626208C>T NC_000022.10:g.51064636C>T NG_009260.2:g.6972G>A - Protein change
- E309K, E223K
- Other names
- -
- Canonical SPDI
- NC_000022.11:50626207:C:T
-
Functional
consequence HelpThe 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 0 to <2% of wild type is taken as severe and likely contributes to disease. [submitted by Gelb Laboratory, University of Washington]
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Global minor allele
frequency (GMAF) HelpThe 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) 0.00002
The Genome Aggregation Database (gnomAD) 0.00004
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 1, 2023 | RCV000058994.13 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Sep 27, 2023 | RCV001039188.10 |
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
(-)
|
criteria provided, single submitter
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: SCV001573212.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Sex: male
|
|
|
Pathogenic
(Jun 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Metachromatic leukodystrophy
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004020642.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
Variant summary: ARSA c.925G>A (p.Glu309Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: ARSA c.925G>A (p.Glu309Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246094 control chromosomes (gnomAD). c.925G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Metachromatic Leukodystrophy (e.g. Biffi_2008, Cesani_2015, Guo_2020, Santhanakumaran_2022). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function in vitro and found the variant effect results in <10% of normal activity, even when overexpressed (e.g. Cesani_2009, Bohringer_2017). The following publications have been ascertained in the context of this evaluation (PMID: 18786133, 19606494, 26462614, 32875726, 36240581, 28762252). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Sep 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Metachromatic leukodystrophy
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001202704.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 68162). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more)
ClinVar contains an entry for this variant (Variation ID: 68162). 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) performed at Invitae indicates that this missense variant is expected to disrupt ARSA protein function. Experimental studies have shown that this missense change affects ARSA function (PMID: 19606494, 27904824, 28762252). For these reasons, this variant has been classified as Pathogenic. This variant is also known as p.Glu307Lys. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 309 of the ARSA protein (p.Glu309Lys). This variant is present in population databases (rs199476360, gnomAD 0.008%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 18768108, 19606494, 26462614, 30057904). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. (less)
|
|
|
Pathogenic
(Nov 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004155286.10
First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024 |
Comment:
ARSA: PM3:Very Strong, PM1, PM2, PM5, PS3:Supporting
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Aug 20, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001875120.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
Comment:
In vitro assays of E309K demonstrate that this variant abolishes ARSA activity (Cesani et al., 2009; Ozkan et al., 2016; Bohringer et al., 2017); Not … (more)
In vitro assays of E309K demonstrate that this variant abolishes ARSA activity (Cesani et al., 2009; Ozkan et al., 2016; Bohringer et al., 2017); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as E307K; This variant is associated with the following publications: (PMID: 28762252, 26462614, 33855715, Hassannejad_2020, 32875726, 30057904, 33385934, 19606494, 27904824, 18768108) (less)
|
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
not provided
|
UniProtKB/Swiss-Prot
Accession: SCV000090515.1
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: SCV005046511.1
First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024 |
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:
1.36% of wild type enzymatic activity
|
Comment:
Comment:
ClinVar contains an entry for this variant (Variation ID: 68162). 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) performed at Invitae indicates that this missense variant is expected to disrupt ARSA protein function. Experimental studies have shown that this missense change affects ARSA function (PMID: 19606494, 27904824, 28762252). For these reasons, this variant has been classified as Pathogenic. This variant is also known as p.Glu307Lys. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 309 of the ARSA protein (p.Glu309Lys). This variant is present in population databases (rs199476360, gnomAD 0.008%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 18768108, 19606494, 26462614, 30057904). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant.
Comment:
ARSA: PM3:Very Strong, PM1, PM2, PM5, PS3:Supporting
Comment:
In vitro assays of E309K demonstrate that this variant abolishes ARSA activity (Cesani et al., 2009; Ozkan et al., 2016; Bohringer et al., 2017); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as E307K; This variant is associated with the following publications: (PMID: 28762252, 26462614, 33855715, Hassannejad_2020, 32875726, 30057904, 33385934, 19606494, 27904824, 18768108)
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
|
Method citation(s):
|
|
Gelb Laboratory, University of Washington
Accession: SCV005046511.1
|
Comment:
As described in PMID: 37480112, ARSA enzymatic activity of 0 to <2% of wild type is taken as severe and likely contributes to disease.
|
Comment:
Variant summary: ARSA c.925G>A (p.Glu309Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246094 control chromosomes (gnomAD). c.925G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Metachromatic Leukodystrophy (e.g. Biffi_2008, Cesani_2015, Guo_2020, Santhanakumaran_2022). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function in vitro and found the variant effect results in <10% of normal activity, even when overexpressed (e.g. Cesani_2009, Bohringer_2017). The following publications have been ascertained in the context of this evaluation (PMID: 18786133, 19606494, 26462614, 32875726, 36240581, 28762252). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
ClinVar contains an entry for this variant (Variation ID: 68162). 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) performed at Invitae indicates that this missense variant is expected to disrupt ARSA protein function. Experimental studies have shown that this missense change affects ARSA function (PMID: 19606494, 27904824, 28762252). For these reasons, this variant has been classified as Pathogenic. This variant is also known as p.Glu307Lys. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 309 of the ARSA protein (p.Glu309Lys). This variant is present in population databases (rs199476360, gnomAD 0.008%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 18768108, 19606494, 26462614, 30057904). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant.
Comment:
ARSA: PM3:Very Strong, PM1, PM2, PM5, PS3:Supporting
Comment:
In vitro assays of E309K demonstrate that this variant abolishes ARSA activity (Cesani et al., 2009; Ozkan et al., 2016; Bohringer et al., 2017); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as E307K; This variant is associated with the following publications: (PMID: 28762252, 26462614, 33855715, Hassannejad_2020, 32875726, 30057904, 33385934, 19606494, 27904824, 18768108)
Citations for germline classification of this variant
Help| 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 |
| Predicting clinical phenotypes of metachromatic leukodystrophy based on the arylsulfatase A activity and the ARSA genotype? - Chances and challenges. | Santhanakumaran V | Molecular genetics and metabolism | 2022 | PMID: 36240581 |
| Identification of a missense ARSA mutation in metachromatic leukodystrophy and its potential pathogenic mechanism. | Guo L | Molecular genetics & genomic medicine | 2020 | PMID: 32875726 |
| Metachromatic leukodystrophy genotypes in The Netherlands reveal novel pathogenic ARSA variants in non-Caucasian patients. | Beerepoot S | Neurogenetics | 2020 | PMID: 32632536 |
| Identification of Novel ARSA Mutations in Chinese Patients with Metachromatic Leukodystrophy. | Chen L | International journal of genomics | 2018 | PMID: 30057904 |
| Enzymatic characterization of novel arylsulfatase A variants using human arylsulfatase A-deficient immortalized mesenchymal stromal cells. | Böhringer J | Human mutation | 2017 | PMID: 28762252 |
| Metachromatic leukodystrophy: Biochemical characterization of two (p.307Glu→Lys, p.318Trp→Cys) arylsulfatase A mutations. | Özkan A | Intractable & rare diseases research | 2016 | PMID: 27904824 |
| Mutation Update of ARSA and PSAP Genes Causing Metachromatic Leukodystrophy. | Cesani M | Human mutation | 2016 | PMID: 26462614 |
| Characterization of new arylsulfatase A gene mutations reinforces genotype-phenotype correlation in metachromatic leukodystrophy. | Cesani M | Human mutation | 2009 | PMID: 19606494 |
| Identification of two novel arylsulfatase A mutations with a polymorphism as a cause of metachromatic leukodystrophy. | Onder E | Neurological research | 2009 | PMID: 18768108 |
| Metachromatic leukodystrophy - mutation analysis provides further evidence of genotype-phenotype correlation. | Biffi A | Clinical genetics | 2008 | PMID: 18786133 |
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Text-mined citations for rs199476360 ...
HelpThese 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
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.