NM_000487.6(ARSA):c.979G>A (p.Gly327Ser) AND Metachromatic leukodystrophy

Clinical significance:Pathogenic (Last evaluated: Jun 4, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000984246.2

Allele description [Variation Report for NM_000487.6(ARSA):c.979G>A (p.Gly327Ser)]

NM_000487.6(ARSA):c.979G>A (p.Gly327Ser)

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.979G>A (p.Gly327Ser)
HGVS:
  • NC_000022.11:g.50626154C>T
  • NG_009260.2:g.7026G>A
  • NM_000487.6:c.979G>AMANE SELECT
  • NM_001085425.3:c.979G>A
  • NM_001085426.3:c.979G>A
  • NM_001085427.3:c.979G>A
  • NM_001085428.3:c.721G>A
  • NM_001362782.2:c.721G>A
  • NP_000478.3:p.Gly327Ser
  • NP_001078894.2:p.Gly327Ser
  • NP_001078895.2:p.Gly327Ser
  • NP_001078896.2:p.Gly327Ser
  • NP_001078897.1:p.Gly241Ser
  • NP_001349711.1:p.Gly241Ser
  • NC_000022.10:g.51064582C>T
  • NM_000487.5:c.979G>A
Protein change:
G241S
Links:
dbSNP: rs148092995
NCBI 1000 Genomes Browser:
rs148092995
Molecular consequence:
  • NM_000487.6:c.979G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085425.3:c.979G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085426.3:c.979G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085427.3:c.979G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085428.3:c.721G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001362782.2:c.721G>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
SCV001132339Counsylno assertion criteria providedLikely pathogenic
(Apr 11, 2019)
unknownclinical testing

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

SCV001588978Invitaecriteria provided, single submitter
Pathogenic
(Jun 4, 2020)
germlineclinical testing

PubMed (6)
[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

Genotypic characterization of Brazilian patients with infantile and juvenile forms of metachromatic leukodystrophy.

Virgens MY, Siebert M, Bock H, Burin M, Giugliani R, Saraiva-Pereira ML.

Gene. 2015 Aug 15;568(1):69-75. doi: 10.1016/j.gene.2015.05.016. Epub 2015 May 9.

PubMed [citation]
PMID:
25965562

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
See all PubMed Citations (7)

Details of each submission

From Counsyl, SCV001132339.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001588978.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces glycine with serine at codon 327 of the ARSA protein (p.Gly327Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant also falls at the last nucleotide of exon 5 of the ARSA coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs148092995, ExAC 0.02%). This variant has been observed to be homozygous or in combination with another ARSA variant in individuals affected with metachromatic leukodystrophy (PMID: 14517960, 26462614, 28762252). This variant is also known in the literature as c.973G>A (p.Gly325Ser). ClinVar contains an entry for this variant (Variation ID: 372303). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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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