NM_000487.6(ARSA):c.1107G>C (p.Lys369Asn) AND Metachromatic leukodystrophy

Clinical significance:Uncertain significance (Last evaluated: May 2, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001216197.2

Allele description [Variation Report for NM_000487.6(ARSA):c.1107G>C (p.Lys369Asn)]

NM_000487.6(ARSA):c.1107G>C (p.Lys369Asn)

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.1107G>C (p.Lys369Asn)
HGVS:
  • NC_000022.11:g.50625936C>G
  • NG_009260.2:g.7244G>C
  • NM_000487.6:c.1107G>CMANE SELECT
  • NM_001085425.3:c.1107G>C
  • NM_001085426.3:c.1107G>C
  • NM_001085427.3:c.1107G>C
  • NM_001085428.3:c.849G>C
  • NM_001362782.2:c.849G>C
  • NP_000478.3:p.Lys369Asn
  • NP_001078894.2:p.Lys369Asn
  • NP_001078895.2:p.Lys369Asn
  • NP_001078896.2:p.Lys369Asn
  • NP_001078897.1:p.Lys283Asn
  • NP_001349711.1:p.Lys283Asn
  • NC_000022.10:g.51064364C>G
  • NM_000487.5:c.1107G>C
Protein change:
K283N
Links:
UniProtKB/Swiss-Prot: VAR_007279; dbSNP: rs199476369
NCBI 1000 Genomes Browser:
rs199476369
Molecular consequence:
  • NM_000487.6:c.1107G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085425.3:c.1107G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085426.3:c.1107G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085427.3:c.1107G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085428.3:c.849G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001362782.2:c.849G>C - 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
SCV001387979Invitaecriteria provided, single submitter
Uncertain significance
(May 2, 2019)
germlineclinical testing

PubMed (4)
[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

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

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]
PMID:
17576681
PMCID:
PMC1934990
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001387979.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces lysine with asparagine at codon 369 of the ARSA protein (p.Lys369Asn). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant also falls at the last nucleotide of exon 6 of the ARSA coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with metachromatic leukodystrophy (PMID: 9090526). ClinVar contains an entry for this variant (Variation ID: 68112). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Nov 27, 2021

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