NM_000487.6(ARSA):c.946G>A (p.Ala316Thr) AND Metachromatic leukodystrophy

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Nov 13, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV000665708.4

Allele description [Variation Report for NM_000487.6(ARSA):c.946G>A (p.Ala316Thr)]

NM_000487.6(ARSA):c.946G>A (p.Ala316Thr)

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.946G>A (p.Ala316Thr)

HGVS:

NC_000022.11:g.50626187C>T
NG_009260.2:g.6993G>A
NM_000487.6:c.946G>AMANE SELECT
NM_001085425.3:c.946G>A
NM_001085426.3:c.946G>A
NM_001085427.3:c.946G>A
NM_001085428.3:c.688G>A
NM_001362782.2:c.688G>A
NP_000478.3:p.Ala316Thr
NP_001078894.2:p.Ala316Thr
NP_001078895.2:p.Ala316Thr
NP_001078896.2:p.Ala316Thr
NP_001078897.1:p.Ala230Thr
NP_001349711.1:p.Ala230Thr
NC_000022.10:g.51064615C>T
NM_000487.5:c.946G>A

Protein change:

A230T

Links:

UniProtKB/Swiss-Prot: VAR_007276; dbSNP: rs199476368

NCBI 1000 Genomes Browser:

rs199476368

Molecular consequence:

NM_000487.6:c.946G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001085425.3:c.946G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001085426.3:c.946G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001085427.3:c.946G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001085428.3:c.688G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001362782.2:c.688G>A - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

functionally_normal [Sequence Ontology: SO:0002219] - Comment(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000789872	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Feb 24, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV004300064	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 13, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 9090526, 28492532
SCV005046507	Gelb Laboratory, University of Washington	no classification provided	not provided	not applicable	in vitro	PubMed (2) [See all records that cite these PMIDs] 9090526, 37480112

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000789872

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Uncertain significance
(Feb 24, 2017)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV004300064

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 13, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV005046507

Gelb Laboratory, University of Washington

no classification provided

not provided

not applicable

in vitro

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	in vitro
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Metachromatic leukodystrophy: identification of the first deletion in exon 1 and of nine novel point mutations in the arylsulfatase A gene.

Draghia R, Letourneur F, Drugan C, Manicom J, Blanchot C, Kahn A, Poenaru L, Caillaud C.

Hum Mutat. 1997;9(3):234-42.

PubMed [citation]

PMID:: 9090526

See all PubMed Citations (3)

Details of each submission

From Counsyl, SCV000789872.1

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004300064.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 68167). This variant is also known as A314T. This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 9090526). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 316 of the ARSA protein (p.Ala316Thr).

#	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 Gelb Laboratory, University of Washington, SCV005046507.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	in vitro	PubMed (2)

Description

"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"

PubMed [ID: 37480112]

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

Last Updated: Sep 29, 2024

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