NM_000487.6(ARSA):c.304del (p.Leu102fs) AND Metachromatic leukodystrophy

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: May 25, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000169476.3

Allele description [Variation Report for NM_000487.6(ARSA):c.304del (p.Leu102fs)]

NM_000487.6(ARSA):c.304del (p.Leu102fs)

Gene:
ARSA:arylsulfatase A [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
22q13.33
Genomic location:
Preferred name:
NM_000487.6(ARSA):c.304del (p.Leu102fs)
HGVS:
  • NC_000022.11:g.50627328del
  • NG_009260.2:g.5853del
  • NM_000487.6:c.304delMANE SELECT
  • NM_001085425.3:c.304del
  • NM_001085426.3:c.304del
  • NM_001085427.3:c.304del
  • NM_001085428.3:c.46del
  • NM_001362782.2:c.46del
  • NP_000478.3:p.Leu102fs
  • NP_001078894.2:p.Leu102fs
  • NP_001078895.2:p.Leu102fs
  • NP_001078896.2:p.Leu102fs
  • NP_001078897.1:p.Leu16fs
  • NP_001349711.1:p.Leu16fs
  • NC_000022.10:g.51065755del
  • NC_000022.10:g.51065756del
  • NM_000487.5:c.304delC
Protein change:
L102fs
Links:
dbSNP: rs786204673
NCBI 1000 Genomes Browser:
rs786204673
Molecular consequence:
  • NM_000487.6:c.304del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001085425.3:c.304del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001085426.3:c.304del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001085427.3:c.304del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001085428.3:c.46del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001362782.2:c.46del - 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
SCV000220922Counsylcriteria provided, single submitter
Likely pathogenic
(Nov 26, 2014)
unknownliterature only

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

Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015),

Citation Link,

SCV000918482Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Dec 26, 2017)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV001592680Invitaecriteria provided, single submitter
Pathogenic
(May 25, 2020)
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
not providedunknownunknownnot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Molecular genetics of metachromatic leukodystrophy.

Gieselmann V, Zlotogora J, Harris A, Wenger DA, Morris CP.

Hum Mutat. 1994;4(4):233-42. Review.

PubMed [citation]
PMID:
7866401

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
See all PubMed Citations (6)

Details of each submission

From Counsyl, SCV000220922.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000918482.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Variant summary: The ARSA c.304delC (p.Leu102CysfsX6) variant results in a premature termination codon, predicted to cause a truncated or absent ARSA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.960G>A/Trp320X). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 190968 control chromosomes. It has been reported in at least one late-infantile metachromatic leukodystrophy patient as a compound heterozygote, and this patient had a residual arylsulfatase A (ARSA) activity <10% of WT level (Kreysing_1993). In addition, one other clinical diagnostic laboratory classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic.

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

From Invitae, SCV001592680.1

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

Description

This sequence change creates a premature translational stop signal (p.Leu102Cysfs*6) in the ARSA gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with metachromatic leukodystrophy (PMID: 8101038). ClinVar contains an entry for this variant (Variation ID: 189073). Loss-of-function variants in ARSA are known to be pathogenic (PMID: 8962139, 10477432). 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: Jun 14, 2021

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