NM_000487.6(ARSA):c.922T>C (p.Tyr308His) AND Metachromatic leukodystrophy

Clinical significance:Conflicting interpretations of pathogenicity, Pathogenic(1);Uncertain significance(1) (Last evaluated: Jul 16, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000670369.2

Allele description [Variation Report for NM_000487.6(ARSA):c.922T>C (p.Tyr308His)]

NM_000487.6(ARSA):c.922T>C (p.Tyr308His)

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.922T>C (p.Tyr308His)
HGVS:
  • NC_000022.11:g.50626211A>G
  • NG_009260.2:g.6969T>C
  • NM_000487.6:c.922T>CMANE SELECT
  • NM_001085425.3:c.922T>C
  • NM_001085426.3:c.922T>C
  • NM_001085427.3:c.922T>C
  • NM_001085428.3:c.664T>C
  • NM_001362782.2:c.664T>C
  • NP_000478.3:p.Tyr308His
  • NP_001078894.2:p.Tyr308His
  • NP_001078895.2:p.Tyr308His
  • NP_001078896.2:p.Tyr308His
  • NP_001078897.1:p.Tyr222His
  • NP_001349711.1:p.Tyr222His
  • NC_000022.10:g.51064639A>G
  • NM_000487.5:c.922T>C
Protein change:
Y222H
Links:
UniProtKB/Swiss-Prot: VAR_054198; dbSNP: rs199476379
NCBI 1000 Genomes Browser:
rs199476379
Molecular consequence:
  • NM_000487.6:c.922T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085425.3:c.922T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085426.3:c.922T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085427.3:c.922T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085428.3:c.664T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001362782.2:c.664T>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
SCV000795212Counsylcriteria provided, single submitter
Uncertain significance
(Nov 6, 2017)
unknownclinical testing

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

Citation Link,

SCV001588980Invitaecriteria provided, single submitter
Pathogenic
(Jul 16, 2020)
germlineclinical testing

PubMed (3)
[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 providedclinical testing

Citations

PubMed

Identification of nine novel arylsulfatase a (ARSA) gene mutations in patients with metachromatic leukodystrophy (MLD).

Eng B, Nakamura LN, O'Reilly N, Schokman N, Nowaczyk MM, Krivit W, Waye JS.

Hum Mutat. 2003 Nov;22(5):418-9.

PubMed [citation]
PMID:
14517960

Biochemical profiling to predict disease severity in metachromatic leukodystrophy.

Tan MA, Fuller M, Zabidi-Hussin ZA, Hopwood JJ, Meikle PJ.

Mol Genet Metab. 2010 Feb;99(2):142-8. doi: 10.1016/j.ymgme.2009.09.006. Epub 2009 Sep 15.

PubMed [citation]
PMID:
19815439
See all PubMed Citations (3)

Details of each submission

From Counsyl, SCV000795212.1

#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 Invitae, SCV001588980.1

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

Description

This sequence change replaces tyrosine with histidine at codon 308 of the ARSA protein (p.Tyr308His). The tyrosine residue is moderately conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with metachromatic leukodystrophy (PMID: 14517960, 19815439). It is also known as Tyr306His or Y306H in the literature. ClinVar contains an entry for this variant (Variation ID: 68161). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ARSA protein function. 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 7, 2021

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