NM_000487.6(ARSA):c.449C>G (p.Pro150Arg) AND Metachromatic leukodystrophy

Clinical significance:Likely pathogenic (Last evaluated: Jan 20, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000698866.4

Allele description [Variation Report for NM_000487.6(ARSA):c.449C>G (p.Pro150Arg)]

NM_000487.6(ARSA):c.449C>G (p.Pro150Arg)

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.449C>G (p.Pro150Arg)
HGVS:
  • NC_000022.11:g.50627182G>C
  • NG_009260.2:g.5998C>G
  • NM_000487.6:c.449C>GMANE SELECT
  • NM_001085425.3:c.449C>G
  • NM_001085426.3:c.449C>G
  • NM_001085427.3:c.449C>G
  • NM_001085428.3:c.191C>G
  • NM_001362782.2:c.191C>G
  • NP_000478.3:p.Pro150Arg
  • NP_001078894.2:p.Pro150Arg
  • NP_001078895.2:p.Pro150Arg
  • NP_001078896.2:p.Pro150Arg
  • NP_001078897.1:p.Pro64Arg
  • NP_001349711.1:p.Pro64Arg
  • NC_000022.10:g.51065610G>C
  • NM_000487.5:c.449C>G
Protein change:
P150R
Links:
dbSNP: rs199476375
NCBI 1000 Genomes Browser:
rs199476375
Molecular consequence:
  • NM_000487.6:c.449C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085425.3:c.449C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085426.3:c.449C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085427.3:c.449C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085428.3:c.191C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001362782.2:c.191C>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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000827555Invitaecriteria provided, single submitter
Likely pathogenic
(Jan 20, 2020)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Mutation Update of ARSA and PSAP Genes Causing Metachromatic Leukodystrophy.

Cesani M, Lorioli L, Grossi S, Amico G, Fumagalli F, Spiga I, Filocamo M, Biffi A.

Hum Mutat. 2016 Jan;37(1):16-27. doi: 10.1002/humu.22919. Epub 2015 Nov 4. Review.

PubMed [citation]
PMID:
26462614

A closer look at ARSA activity in a patient with metachromatic leukodystrophy.

Doherty K, Frazier SB, Clark M, Childers A, Pruthi S, Wenger DA, Duis J.

Mol Genet Metab Rep. 2019 Jun;19:100460. doi: 10.1016/j.ymgmr.2019.100460.

PubMed [citation]
PMID:
30828547
PMCID:
PMC6383325
See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000827555.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces proline with arginine at codon 150 of the ARSA protein (p.Pro150Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported as homozygous in an individual affected with metachromatic leukodystrophy (PMID: 26462614, 30828547) as well as the presymptomatic sibling (PMID: 23845948). This variant is also known as p.Pro148Arg in the literature. ClinVar contains an entry for this variant (Variation ID: 576385). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). This variant disrupts the p.Pro150 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been observed in individuals with ARSA-related conditions (PMID: 10381328, 18786133), which suggests that this may be a clinically significant amino acid residue. 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 7, 2021

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