NM_000487.6(ARSA):c.917C>T (p.Thr306Met) AND Metachromatic leukodystrophy

Clinical significance:Conflicting interpretations of pathogenicity, Pathogenic(3);Uncertain significance(1) (Last evaluated: May 20, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000578460.5

Allele description [Variation Report for NM_000487.6(ARSA):c.917C>T (p.Thr306Met)]

NM_000487.6(ARSA):c.917C>T (p.Thr306Met)

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.917C>T (p.Thr306Met)
HGVS:
  • NC_000022.11:g.50626216G>A
  • NG_009260.2:g.6964C>T
  • NM_000487.6:c.917C>TMANE SELECT
  • NM_001085425.3:c.917C>T
  • NM_001085426.3:c.917C>T
  • NM_001085427.3:c.917C>T
  • NM_001085428.3:c.659C>T
  • NM_001362782.2:c.659C>T
  • NP_000478.3:p.Thr306Met
  • NP_001078894.2:p.Thr306Met
  • NP_001078895.2:p.Thr306Met
  • NP_001078896.2:p.Thr306Met
  • NP_001078897.1:p.Thr220Met
  • NP_001349711.1:p.Thr220Met
  • NC_000022.10:g.51064644G>A
  • NM_000487.5:c.917C>T
Protein change:
T220M
Links:
UniProtKB/Swiss-Prot: VAR_067416; dbSNP: rs199476359
NCBI 1000 Genomes Browser:
rs199476359
Molecular consequence:
  • NM_000487.6:c.917C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085425.3:c.917C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085426.3:c.917C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085427.3:c.917C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085428.3:c.659C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001362782.2:c.659C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

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
SCV000680145Institute of Human Genetics, Klinikum rechts der Isarcriteria provided, single submitter
Pathogenic
(Sep 8, 2017)
paternalclinical testing

Citation Link,

SCV000800270Counsylcriteria provided, single submitter
Uncertain significance
(May 29, 2018)
unknownclinical testing

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

Citation Link,

SCV001370552Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(May 5, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV001398115Invitaecriteria provided, single submitter
Pathogenic
(May 20, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedpaternalyes1not providednot provided1not providedclinical testing

Citations

PubMed

Early prenatal diagnosis of lysosomal storage disorders by enzymatic and molecular analysis.

Li D, Lin Y, Huang Y, Zhang W, Jiang M, Li X, Zhao X, Sheng H, Yin X, Su X, Shao Y, Liu Z, Li D, Li F, Liao C, Liu L.

Prenat Diagn. 2018 Sep;38(10):779-787. doi: 10.1002/pd.5329. Epub 2018 Jul 17. Erratum in: Prenat Diagn. 2019 Jan;39(1):57.

PubMed [citation]
PMID:
29966168

Thickening of the optic nerves in metachromatic leucodystrophy: A new MRI finding.

Roi D, Mankad K, Kaliakatsos M, Cleary M, Manzur A, D'Arco F.

Neuroradiol J. 2016 Apr;29(2):134-6. doi: 10.1177/1971400916633479. Epub 2016 Feb 25.

PubMed [citation]
PMID:
26915897
PMCID:
PMC4978318
See all PubMed Citations (6)

Details of each submission

From Institute of Human Genetics, Klinikum rechts der Isar, SCV000680145.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1paternalyes1bloodnot provided1not providednot providednot provided

From Counsyl, SCV000800270.1

#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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001370552.1

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

Description

Variant summary: ARSA c.917C>T (p.Thr306Met) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 247446 control chromosomes (gnomAD). c.917C>T has been reported in the literature in individuals affected with Metachromatic Leukodystrophy (e.g. Biffi_2008, Chen_2018, Li_2018). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated null residual enzyme activity for the variant in different cellular systems (Cesani_2009). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=1) and as uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

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

From Invitae, SCV001398115.2

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

Description

This sequence change replaces threonine with methionine at codon 306 of the ARSA protein (p.Thr306Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another ARSA variant in individual(s) with metachromatic leukodystrophy (PMID: 18786133, 30057904, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 911C>T (Thr304Met) in the literature. ClinVar contains an entry for this variant (Variation ID: 68159). This variant has been reported to affect ARSA protein function (PMID: 19606494). 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 16, 2021

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