NM_000487.6(ARSA):c.1227_1228del (p.Thr410fs) AND Metachromatic leukodystrophy

Clinical significance:Likely pathogenic (Last evaluated: Dec 7, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001280565.1

Allele description [Variation Report for NM_000487.6(ARSA):c.1227_1228del (p.Thr410fs)]

NM_000487.6(ARSA):c.1227_1228del (p.Thr410fs)

Gene:
ARSA:arylsulfatase A [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
22q13.33
Genomic location:
Preferred name:
NM_000487.6(ARSA):c.1227_1228del (p.Thr410fs)
HGVS:
  • NC_000022.11:g.50625448_50625449del
  • NG_009260.2:g.7732_7733del
  • NM_000487.6:c.1227_1228delMANE SELECT
  • NM_001085425.3:c.1227_1228del
  • NM_001085426.3:c.1227_1228del
  • NM_001085427.3:c.1227_1228del
  • NM_001085428.3:c.969_970del
  • NM_001362782.2:c.969_970del
  • NP_000478.3:p.Thr410fs
  • NP_001078894.2:p.Thr410fs
  • NP_001078895.2:p.Thr410fs
  • NP_001078896.2:p.Thr410fs
  • NP_001078897.1:p.Thr324fs
  • NP_001349711.1:p.Thr324fs
  • NC_000022.10:g.51063876_51063877del
  • NM_000487.5:c.1227_1228delTA
Protein change:
T324fs
Molecular consequence:
  • NM_000487.6:c.1227_1228del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001085425.3:c.1227_1228del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001085426.3:c.1227_1228del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001085427.3:c.1227_1228del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001085428.3:c.969_970del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001362782.2:c.969_970del - 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
SCV001467767Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Dec 7, 2020)
germlineclinical testing

Citation Link

Summary from all submissions

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

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001467767.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Variant summary: ARSA c.1227_1228delTA (p.Thr410HisfsX16) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant was absent in 238760 control chromosomes. c.1227_1228delTA has been reported in the literature as 2324delAT in at-least one homozygous individual affected with the late infantile form of Metachromatic Leukodystrophy (Regis_1995). At least one publication reports experimental evidence evaluating enzyme activity in cultured fibroblasts. However, this report does not allow convincing conclusions about the variant effect due to no information on a reference range for control activity levels (Regis_1995). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

Last Updated: Jun 14, 2021

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