NM_012208.3(HARS2):c.598C>G (p.Leu200Val) AND Perrault syndrome 2

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Pathogenic(1) (Last evaluated: Jun 27, 2013)

Review status:(0/4) 0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000032820.6

Allele description

NM_012208.3(HARS2):c.598C>G (p.Leu200Val)

Gene:
HARS2:histidyl-tRNA synthetase 2, mitochondrial [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
5q31.3
Genomic location:
Preferred name:
NM_012208.3(HARS2):c.598C>G (p.Leu200Val)
HGVS:
  • NC_000005.10:g.140695810C>G
  • NG_021415.1:g.9378C>G
  • NM_012208.3:c.598C>G
  • NP_036340.1:p.Leu200Val
  • NC_000005.9:g.140075395C>G
  • NM_012208.2:c.598C>G
  • P49590:p.Leu200Val
Protein change:
L200V; LEU200VAL
Links:
UniProtKB: P49590#VAR_069532; OMIM: 600783.0001; dbSNP: rs397515410
NCBI 1000 Genomes Browser:
rs397515410
Molecular consequence:
  • NM_012208.3:c.598C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Perrault syndrome 2 (PRLTS2)
Identifiers:
MedGen: C3554105; Orphanet: 2855; OMIM: 614926

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000056588OMIMno assertion criteria providedPathogenic
(Apr 19, 2011)
germlineliterature only

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

SCV000243998ClinVar Staff, National Center for Biotechnology Information (NCBI)no assertion criteria providedLikely pathogenic
(Jun 27, 2013)
germlineliterature only

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedliterature only
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

The Perrault syndrome: autosomal recessive ovarian dysgenesis with facultative, non-sex-limited sensorineural deafness.

Pallister PD, Opitz JM.

Am J Med Genet. 1979;4(3):239-46.

PubMed [citation]
PMID:
517579

Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome.

Pierce SB, Chisholm KM, Lynch ED, Lee MK, Walsh T, Opitz JM, Li W, Klevit RE, King MC.

Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6543-8. doi: 10.1073/pnas.1103471108. Epub 2011 Apr 4.

PubMed [citation]
PMID:
21464306
PMCID:
PMC3081023

Details of each submission

From OMIM, SCV000056588.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (2)

Description

In affected members of a family of European descent with Perrault syndrome-2 (PRLTS2; 614926), originally reported by Pallister and Opitz (1979), Pierce et al. (2011) identified compound heterozygosity for 2 mutations in the HARS2 gene: a paternally inherited 598C-G transversion in exon 6 resulting in a leu200-to-val (L200V) substitution at a highly conserved residue, and a maternally inherited 1102G-T transversion in exon 10 resulting in a val368-to-leu (V368L; 600783.0002) substitution at a highly conserved residue. The mutations were found by linkage analysis followed by candidate gene sequencing. Neither mutation was found in 1,942 control individuals. Study of patient lymphoblasts showed that the 598C-G mutation also created an alternative splice site, resulting in an in-frame deletion of 12 codons in exon 6 (delta200-211). The deletion transcript was present at much lower levels in the unaffected father compared to the affected children. Both mutant missense proteins were expressed, could dimerize, and localized to the mitochondria in mammalian cells, but the deletion transcript was poorly expressed, suggesting that it is unstable. Both missense mutations had significantly decreased enzymatic activity compared to wildtype, with the V368L mutation showing a more severe effect. Modeling of the homologous mutations in yeast also indicated that the V368L mutant had a more severe effect on enzyme activity. Based on the functions of mitochondrial tRNA synthetases and cellular defects resulting from their mutation, Pierce et al. (2011) speculated that mutations in HARS2 result in decreased mitochondrial translation and respiratory chain defects in affected tissues.

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

From ClinVar Staff, National Center for Biotechnology Information (NCBI), SCV000243998.1

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

Last Updated: Sep 5, 2017