NM_000487.6(ARSA):c.526C>T (p.Gln176Ter) AND Metachromatic leukodystrophy

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jun 18, 2023
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:: RCV000409359.7

Allele description [Variation Report for NM_000487.6(ARSA):c.526C>T (p.Gln176Ter)]

NM_000487.6(ARSA):c.526C>T (p.Gln176Ter)

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.526C>T (p.Gln176Ter)

HGVS:

NC_000022.11:g.50626992G>A
NG_009260.2:g.6188C>T
NM_000487.6:c.526C>TMANE SELECT
NM_001085425.3:c.526C>T
NM_001085426.3:c.526C>T
NM_001085427.3:c.526C>T
NM_001085428.3:c.268C>T
NM_001362782.2:c.268C>T
NP_000478.3:p.Gln176Ter
NP_001078894.2:p.Gln176Ter
NP_001078895.2:p.Gln176Ter
NP_001078896.2:p.Gln176Ter
NP_001078897.1:p.Gln90Ter
NP_001349711.1:p.Gln90Ter
NC_000022.10:g.51065420G>A
NM_000487.5:c.526C>T
p.Gln176Ter

Protein change:

Q176*

Links:

dbSNP: rs762284875

NCBI 1000 Genomes Browser:

rs762284875

Molecular consequence:

NM_000487.6:c.526C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001085425.3:c.526C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001085426.3:c.526C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001085427.3:c.526C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001085428.3:c.268C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001362782.2:c.268C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

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
SCV000487297	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Nov 9, 2016)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV000930529	Molecular Genetics Laboratory, Faculty of Medicine Siriraj Hospital, Mahidol University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 2, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002141338	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 18, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26553228, 8962139, 10477432, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000487297

Counsyl

criteria provided, single submitter

(Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))

Likely pathogenic
(Nov 9, 2016)

unknown

clinical testing

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

mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf,

Citation Link,

SCV000930529

Molecular Genetics Laboratory, Faculty of Medicine Siriraj Hospital, Mahidol University

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 2, 2019)

germline

clinical testing

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

SCV002141338

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 18, 2023)

germline

clinical testing

PubMed (4)
[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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
East Asian	germline	yes	1	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

Late infantile metachromatic leukodystrophy: Clinical manifestations of five Taiwanese patients and Genetic features in Asia.

Liaw HR, Lee HF, Chi CS, Tsai CR.

Orphanet J Rare Dis. 2015 Nov 9;10:144. doi: 10.1186/s13023-015-0363-1.

PubMed [citation]

PMID:: 26553228
PMCID:: PMC4638099

See all PubMed Citations (5)

Details of each submission

From Counsyl, SCV000487297.2

#	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 Molecular Genetics Laboratory, Faculty of Medicine Siriraj Hospital, Mahidol University, SCV000930529.1

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

Description

The Gln176Ter, a null variant (nonsense) affecting ARSA gene has been reported together with Arg293Ter in one Taiwanese patient with late infantile metachromatic leukodystrophy (Liaw et al., 2015), and was at extremely low frequency in ExAC (0.000009, 1/115950) and GnomAD_exome (0.000008, 2/246212). In our tested patient, Gln176Ter was found in the heterozygous state in unknown phase with a variant of uncertain significance, Arg313Gln. In summary, the Gln176Ter variant meets our criteria to be classified as pathogenic (Richards et al., 2015) based upon a known mechanism of disease, extremely low frequency and the previous reported evidence.

#	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		1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002141338.3

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

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 371662). This premature translational stop signal has been observed in individual(s) with late infantile metachromatic leukodystrophy (PMID: 26553228). This variant is present in population databases (rs762284875, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Gln176*) in the ARSA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ARSA are known to be pathogenic (PMID: 8962139, 10477432).

#	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

Last Updated: Sep 29, 2024

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