NM_000487.6(ARSA):c.338T>C (p.Leu113Pro) AND Metachromatic leukodystrophy

Germline classification:: Likely pathogenic (4 submissions)
Last evaluated:: May 14, 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:: RCV001376979.10

Allele description [Variation Report for NM_000487.6(ARSA):c.338T>C (p.Leu113Pro)]

NM_000487.6(ARSA):c.338T>C (p.Leu113Pro)

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.338T>C (p.Leu113Pro)

HGVS:

NC_000022.11:g.50627293A>G
NG_009260.2:g.5887T>C
NM_000487.6:c.338T>CMANE SELECT
NM_001085425.3:c.338T>C
NM_001085426.2:c.338T>C
NM_001085426.3:c.338T>C
NM_001085427.3:c.338T>C
NM_001085428.3:c.80T>C
NM_001362782.2:c.80T>C
NP_000478.3:p.Leu113Pro
NP_001078894.2:p.Leu113Pro
NP_001078895.2:p.Leu113Pro
NP_001078896.2:p.Leu113Pro
NP_001078897.1:p.Leu27Pro
NP_001349711.1:p.Leu27Pro
NC_000022.10:g.51065721A>G
NM_000487.5:c.338T>C

Protein change:

L113P

Links:

dbSNP: rs777431148

NCBI 1000 Genomes Browser:

rs777431148

Molecular consequence:

NM_000487.6:c.338T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001085425.3:c.338T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001085426.3:c.338T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001085427.3:c.338T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001085428.3:c.80T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001362782.2:c.80T>C - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

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

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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MCE-family protein Mce1A [Mycobacterium liflandii 128FXT]
MCE-family protein Mce1A [Mycobacterium liflandii 128FXT]
gi|442581366|gnl|MIUM|MULP_00400|gb 0509.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001574194	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (May 14, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28799099, 28492532
SCV002058597	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] PMID:28799099,
SCV003919158	Rare Genetic Disease Lab, Dept of Zoology, Government Postgraduate College Dargai Malakand, Higher Education Govt. of Khyber Pakhtunkhwa	no assertion criteria provided	Pathogenic (Feb 6, 2023)	germline	clinical testing
SCV005046654	Gelb Laboratory, University of Washington	no classification provided	not provided	not applicable	in vitro	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	1	not provided	clinical testing
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

Citations

PubMed

Metachromatic Leukodystrophy (MLD): a Pakistani Family with Novel ARSA Gene Mutation.

Shahzad MA, Khaliq S, Amar A, Mahmood S.

J Mol Neurosci. 2017 Sep;63(1):84-90. doi: 10.1007/s12031-017-0959-0. Epub 2017 Aug 10.

PubMed [citation]

PMID:: 28799099

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

See all PubMed Citations (4)

PMC

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.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001574194.4

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

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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: 1066073). This missense change has been observed in individual(s) with clinical features of metachromatic leukodystrophy (PMID: 28799099; Invitae). This variant is present in population databases (rs777431148, gnomAD 0.004%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 113 of the ARSA protein (p.Leu113Pro).

#	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 3billion, SCV002058597.1

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

Description

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001066073, PMID:28799099, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.987, 3CNET: 0.985, PP3_P). A missense variant is a common mechanism associated with Metachromatic leukodystrophy (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000005, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

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

From Rare Genetic Disease Lab, Dept of Zoology, Government Postgraduate College Dargai Malakand, Higher Education Govt. of Khyber Pakhtunkhwa, SCV003919158.1

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

From Gelb Laboratory, University of Washington, SCV005046654.1

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

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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