NM_000487.6(ARSA):c.542T>G (p.Ile181Ser) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Apr 1, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000657846.38

Allele description

NM_000487.6(ARSA):c.542T>G (p.Ile181Ser)

Gene:

ARSA:arylsulfatase A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

22q13.33

Genomic location:

Preferred name:

NM_000487.6(ARSA):c.542T>G (p.Ile181Ser)

Other names:

I179S

HGVS:

NC_000022.11:g.50626976A>C
NG_009260.2:g.6204T>G
NM_000487.6:c.542T>GMANE SELECT
NM_001085425.3:c.542T>G
NM_001085426.3:c.542T>G
NM_001085427.3:c.542T>G
NM_001085428.3:c.284T>G
NM_001362782.2:c.284T>G
NP_000478.3:p.Ile181Ser
NP_001078894.2:p.Ile181Ser
NP_001078895.2:p.Ile181Ser
NP_001078896.2:p.Ile181Ser
NP_001078897.1:p.Ile95Ser
NP_001349711.1:p.Ile95Ser
NC_000022.10:g.51065404A>C
NM_000487.4:c.536T>G
NM_000487.5:c.542T>G
p.Ile181Ser

Note:

NCBI staff reviewed the sequence information reported in PubMed 1684088 to determine the location of this allele on current reference sequence.

Protein change:

I181S; ILE179SER

Links:

OMIM: 607574.0008; dbSNP: rs74315457

NCBI 1000 Genomes Browser:

rs74315457

Molecular consequence:

NM_000487.6:c.542T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001085425.3:c.542T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001085426.3:c.542T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001085427.3:c.542T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001085428.3:c.284T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001362782.2:c.284T>G - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

loss_of_function_variant [Sequence Ontology: SO:0002054] - Comment(s)

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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PREDICTED: Homo sapiens adducin 1 (ADD1), transcript variant X5, mRNA
PREDICTED: Homo sapiens adducin 1 (ADD1), transcript variant X5, mRNA
gi|2462594782|ref|XM_054348868.1|

Nucleotide
PREDICTED: Homo sapiens adducin 1 (ADD1), transcript variant X3, mRNA
PREDICTED: Homo sapiens adducin 1 (ADD1), transcript variant X3, mRNA
gi|2217348784|ref|XM_017007703.2|

Nucleotide
alpha-adducin isoform X3 [Homo sapiens]
alpha-adducin isoform X3 [Homo sapiens]
gi|2462594789|ref|XP_054204846.1|

Protein
Homo sapiens adducin 1 (ADD1), transcript variant 5, mRNA
Homo sapiens adducin 1 (ADD1), transcript variant 5, mRNA
gi|1890270885|ref|NM_001286645.2|

Nucleotide
Oribacterium sp. oral taxon 078 str. F0262 Scfld1, whole genome shotgun sequence
Oribacterium sp. oral taxon 078 str. F0262 Scfld1, whole genome shotgun sequence
gi|269215345|ref|NZ_GG729934.1||gnl NZ_ACIQ02|Scfld1

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000228890	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Feb 10, 2015)	germline	clinical testing	Citation Link,
SCV000779603	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (May 18, 2021)	germline	clinical testing	Citation Link,
SCV001245878	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Jan 1, 2022)	germline	clinical testing	Citation Link,
SCV001447975	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001715402	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 1, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] PMID:20301309,
SCV001741024	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001880043	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics criteria)	Pathogenic (Jan 13, 2021)	unknown	clinical testing	PubMed (18) [See all records that cite these PMIDs] 10533072, 1684088, 18786133, 31186049, 26462614, 26890752, 23701968, 18693274, 15952986, 12081727, 9600244, 9096767, 32632536, 33335837, 28762252, 33046606, 16966551, 26467025
SCV001931662	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	12	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	4	not provided	not provided	1	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Metachromatic leucodystrophy: a newly identified mutation in arylsulphatase A, D281Y, found as a compound heterozygote with I179L in an adult onset case.

Halsall DJ, Halligan EP, Elsey TS, Cox TM.

Hum Mutat. 1999 Nov;14(5):447.

PubMed [citation]

PMID:: 10533072

See all PubMed Citations (19)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000228890.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	9	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		9	not provided	not provided	not provided

From GeneDx, SCV000779603.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Published functional studies demonstrate a damaging effect, specifically, I181S results in approximately 5% residual arylsulfatase A activity, compared to wildtype (Fluharty et al., 1991); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12081727, 31684987, 20301309, 9600244, 26462614, 28762252, 26890752, 18786133, 21896413, 30083785, 31186049, 31262576, 18693274, 31980526, 1684088, 9096767, 32632536, 31589614)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001245878.22

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		4	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001447975.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		not provided	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV001715402.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		3	not provided	not provided	not provided

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001741024.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Athena Diagnostics, SCV001880043.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (18)

Description

This variant is one of the most common variants associated with autosomal recessive metachromatic leukodystrophy in the European population (PMID 15952986, 9096767), therefore The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant appears to segregate with disease in at least one family, however, the available information does not rule out segregation due to chance. This variant is also referred to as c.536T>G (p.Ile179Ser) in published literature. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant was shown to significantly reduce arylsulfatase A activity (PMID 1684088). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001931662.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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