NM_000487.6(ARSA):c.1115G>A (p.Arg372Gln) AND Metachromatic leukodystrophy

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(2) (Last evaluated: Apr 12, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000544790.4

Allele description [Variation Report for NM_000487.6(ARSA):c.1115G>A (p.Arg372Gln)]

NM_000487.6(ARSA):c.1115G>A (p.Arg372Gln)

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.1115G>A (p.Arg372Gln)
Other names:
R370Q
HGVS:
  • NC_000022.11:g.50625674C>T
  • NG_009260.2:g.7506G>A
  • NM_000487.6:c.1115G>AMANE SELECT
  • NM_001085425.3:c.1115G>A
  • NM_001085426.3:c.1115G>A
  • NM_001085427.3:c.1115G>A
  • NM_001085428.3:c.857G>A
  • NM_001362782.2:c.857G>A
  • NP_000478.3:p.Arg372Gln
  • NP_001078894.2:p.Arg372Gln
  • NP_001078895.2:p.Arg372Gln
  • NP_001078896.2:p.Arg372Gln
  • NP_001078897.1:p.Arg286Gln
  • NP_001349711.1:p.Arg286Gln
  • NC_000022.10:g.51064102C>T
  • NM_000487.5:c.1115G>A
Protein change:
R286Q; ARG370GLN
Links:
OMIM: 607574.0034; dbSNP: rs74315477
NCBI 1000 Genomes Browser:
rs74315477
Molecular consequence:
  • NM_000487.6:c.1115G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085425.3:c.1115G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085426.3:c.1115G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085427.3:c.1115G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085428.3:c.857G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001362782.2:c.857G>A - 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
SCV000627135Invitaecriteria provided, single submitter
Uncertain significance
(Apr 12, 2017)
germlineclinical testing

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

SCV000800496Counsylcriteria provided, single submitter
Uncertain significance
(Feb 9, 2017)
unknownclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001781530Kasturba Medical College, Manipal, Manipal Academy of Higher Educationcriteria provided, single submitter
Likely pathogenicinheritedclinical testing

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

Summary from all submissions

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

Citations

PubMed

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):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Missense mutations as a cause of metachromatic leukodystrophy. Degradation of arylsulfatase A in the endoplasmic reticulum.

Poeppel P, Habetha M, Marcão A, Büssow H, Berna L, Gieselmann V.

FEBS J. 2005 Mar;272(5):1179-88.

PubMed [citation]
PMID:
15720392
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000627135.1

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

Description

This sequence change replaces arginine with glutamine at codon 372 of the ARSA protein (p.Arg372Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs74315477, ExAC 0.002%). This variant has been reported in the literature in a mildly affected individual (PMID: 7866401). ClinVar contains an entry for this variant (Variation ID: 3082). This variant is also known as p.Arg370Gln or p.R370Q in the literature. 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"). A different missense substitution at this codon (p.Arg370Trp) has been shown to cause diminished enzyme activity in vitro (PMID: 7825603). This suggests that the arginine residue is critical for ARSA protein function and that other missense substitutions at this position may also impact protein function. In summary, this variant is a rare missense change that has been observed in affected individual but has uncertain impact on protein function.  Additional genetic or functional data are needed to assess the clinical relevance of this variant. For these reasons, this change has been classified as a Variant of Uncertain Significance.

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

From Counsyl, SCV000800496.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Kasturba Medical College, Manipal, Manipal Academy of Higher Education, SCV001781530.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1inheritedyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

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