NM_000487.6(ARSA):c.1055A>G (p.Asn352Ser) AND Metachromatic leukodystrophy

Germline classification:: Benign/Likely benign (7 submissions)
Last evaluated:: Feb 1, 2024
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:: RCV000020310.29

Allele description [Variation Report for NM_000487.6(ARSA):c.1055A>G (p.Asn352Ser)]

NM_000487.6(ARSA):c.1055A>G (p.Asn352Ser)

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.1055A>G (p.Asn352Ser)

Other names:

N350S

HGVS:

NC_000022.11:g.50625988T>C
NG_009260.2:g.7192A>G
NM_000487.6:c.1055A>GMANE SELECT
NM_001085425.3:c.1055A>G
NM_001085426.3:c.1055A>G
NM_001085427.3:c.1055A>G
NM_001085428.3:c.797A>G
NM_001362782.2:c.797A>G
NP_000478.3:p.Asn352Ser
NP_000478.3:p.Asn352Ser
NP_001078894.2:p.Asn352Ser
NP_001078895.2:p.Asn352Ser
NP_001078896.2:p.Asn352Ser
NP_001078897.1:p.Asn266Ser
NP_001349711.1:p.Asn266Ser
NC_000022.10:g.51064416T>C
NM_000487.4:c.1049A>G
NM_000487.5:c.1055A>G
NP_000478.2:p.Asn350Ser

Note:

NCBI staff reviewed the sequence information reported in PubMed 2574462 to determine the location of this allele on current reference sequence.

Protein change:

N266S; ASN350SER

Links:

OMIM: 607574.0002; dbSNP: rs2071421

NCBI 1000 Genomes Browser:

rs2071421

Molecular consequence:

NM_000487.6:c.1055A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001085425.3:c.1055A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001085426.3:c.1055A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001085427.3:c.1055A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001085428.3:c.797A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001362782.2:c.797A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Metachromatic leukodystrophy (MLD)
Synonyms:: Metachromatic leukoencephalopathy; Sulfatide lipidosis; Cerebral sclerosis diffuse metachromatic form; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0018868; MedGen: C0023522; Orphanet: 512; OMIM: 250100

Recent activity

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BioSample Links for SRA (Select 4296722) (1)
BioSample
GEO accession GSM2711549 is currently private and is scheduled to be released on...
GEO accession GSM2711549 is currently private and is scheduled to be released on Oct 15, 2020.

biosample
Homo sapiens deltex E3 ubiquitin ligase 4 (DTX4), transcript variant 1, mRNA
Homo sapiens deltex E3 ubiquitin ligase 4 (DTX4), transcript variant 1, mRNA
gi|1519313690|ref|NM_015177.2|

Nucleotide
GEO DataSets Links for BioSample (Select 2418766) (1)
GEO DataSets
UHRF1_hi_A
UHRF1_hi_A

GEO DataSets

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000040685	GeneReviews	no classification provided	not provided	germline	literature only
SCV000439433	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Benign (Mar 6, 2018)	germline	clinical testing	Citation Link,
SCV000883252	SIB Swiss Institute of Bioinformatics	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Oct 15, 2018)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 11941485, 2574462, 25741868
SCV001141462	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Likely benign (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001456232	Natera, Inc.	no assertion criteria provided	Benign (Dec 10, 2019)	germline	clinical testing
SCV001733012	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Benign (Feb 1, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001737289	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Jun 10, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Contribution of arylsulfatase A mutations located on the same allele to enzyme activity reduction and metachromatic leukodystrophy severity.

Regis S, Corsolini F, Stroppiano M, Cusano R, Filocamo M.

Hum Genet. 2002 Apr;110(4):351-5. Epub 2002 Mar 8.

PubMed [citation]

PMID:: 11941485

Arylsulfatase A pseudodeficiency: loss of a polyadenylylation signal and N-glycosylation site.

Gieselmann V, Polten A, Kreysing J, von Figura K.

Proc Natl Acad Sci U S A. 1989 Dec;86(23):9436-40.

PubMed [citation]

PMID:: 2574462
PMCID:: PMC298511

See all PubMed Citations (4)

Details of each submission

From GeneReviews, SCV000040685.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	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		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000439433.3

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

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

#	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		not provided	not provided	not provided	not provided

From SIB Swiss Institute of Bioinformatics, SCV000883252.1

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

Description

This variant is interpreted as Benign - Stand Alone, for Metachromatic leukodystrophy, autosomal recessive. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (https://www.ncbi.nlm.nih.gov/pubmed/11941485) (https://www.ncbi.nlm.nih.gov/pubmed/2574462).

#	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		not provided	not provided	not provided	not provided

From Mendelics, SCV001141462.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001456232.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV001733012.4

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV001737289.1

#	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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 12, 2024

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