NM_000487.6(ARSA):c.1087dup (p.Leu363fs) AND Metachromatic leukodystrophy

Clinical significance:Pathogenic (Last evaluated: Feb 8, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001064269.2

Allele description [Variation Report for NM_000487.6(ARSA):c.1087dup (p.Leu363fs)]

NM_000487.6(ARSA):c.1087dup (p.Leu363fs)

Gene:
ARSA:arylsulfatase A [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
22q13.33
Genomic location:
Preferred name:
NM_000487.6(ARSA):c.1087dup (p.Leu363fs)
HGVS:
  • NC_000022.11:g.50625960dup
  • NG_009260.2:g.7224dup
  • NM_000487.6:c.1087dupMANE SELECT
  • NM_001085425.3:c.1087dup
  • NM_001085426.3:c.1087dup
  • NM_001085427.3:c.1087dup
  • NM_001085428.3:c.829dup
  • NM_001362782.2:c.829dup
  • NP_000478.3:p.Leu363fs
  • NP_001078894.2:p.Leu363fs
  • NP_001078895.2:p.Leu363fs
  • NP_001078896.2:p.Leu363fs
  • NP_001078897.1:p.Leu277fs
  • NP_001349711.1:p.Leu277fs
  • NC_000022.10:g.51064383_51064384insG
  • NC_000022.10:g.51064388dup
  • NM_000487.5:c.1087dup
Protein change:
L277fs
Links:
Molecular consequence:
  • NM_000487.6:c.1087dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001085425.3:c.1087dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001085426.3:c.1087dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001085427.3:c.1087dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001085428.3:c.829dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001362782.2:c.829dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV001229158Invitaecriteria provided, single submitter
Pathogenic
(Feb 8, 2019)
germlineclinical testing

PubMed (5)
[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

Missense mutations in the arylsulphatase A genes of metachromatic leukodystrophy patients.

Barth ML, Fensom A, Harris A.

Hum Mol Genet. 1993 Dec;2(12):2117-21.

PubMed [citation]
PMID:
7906588
See all PubMed Citations (5)

Details of each submission

From Invitae, SCV001229158.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change results in a premature translational stop signal in the ARSA gene (p.Leu363Profs*47). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 147 amino acids of the ARSA protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ARSA-related conditions. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. This variant disrupts the C-terminus of the ARSA protein. Another variant that disrupts this region (p.Pro349Hisfs*74) has been determined to be pathogenic (PMID:26462614, 7906588, 19021637, 10220151). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Oct 7, 2021

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