NM_001031726.3(C19orf12):c.205G>A (p.Gly69Arg) AND Neurodegeneration with brain iron accumulation 4

Clinical significance:Likely pathogenic (Last evaluated: Oct 5, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000024153.7

Allele description [Variation Report for NM_001031726.3(C19orf12):c.205G>A (p.Gly69Arg)]

NM_001031726.3(C19orf12):c.205G>A (p.Gly69Arg)

Gene:
C19orf12:chromosome 19 open reading frame 12 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
19q12
Genomic location:
Preferred name:
NM_001031726.3(C19orf12):c.205G>A (p.Gly69Arg)
Other names:
C19ORF12, GLY69ARG
HGVS:
  • NC_000019.10:g.29702966C>T
  • NG_031970.1:g.17824G>A
  • NG_031970.2:g.17824G>A
  • NM_001031726.3:c.205G>A
  • NM_001256046.2:c.172G>A
  • NM_001256047.1:c.172G>A
  • NM_001282929.1:c.-21G>A
  • NM_001282930.2:c.-21G>A
  • NM_001282931.2:c.-21G>A
  • NM_031448.5:c.172G>A
  • NP_001026896.2:p.Gly69Arg
  • NP_001026896.2:p.Gly69Arg
  • NP_001242975.1:p.Gly58Arg
  • NP_001242976.1:p.Gly58Arg
  • NP_113636.2:p.Gly58Arg
  • NC_000019.9:g.30193873C>T
  • NM_001031726.2:c.205G>A
  • Q9NSK7:p.Gly69Arg
Note:
ClinGen staff contributed the HGVS expression for this variant.
Protein change:
G58R; GLY69ARG
Links:
UniProtKB: Q9NSK7#VAR_066620; OMIM: 614297.0003; dbSNP: rs515726205
NCBI 1000 Genomes Browser:
rs515726205
Molecular consequence:
  • NM_001282929.1:c.-21G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001282930.2:c.-21G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001282931.2:c.-21G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001031726.3:c.205G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001256046.2:c.172G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001256047.1:c.172G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_031448.5:c.172G>A - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
Unknown function
Observations:
1

Condition(s)

Name:
Neurodegeneration with brain iron accumulation 4 (NBIA4)
Synonyms:
MITOCHONDRIAL PROTEIN-ASSOCIATED NEURODEGENERATION
Identifiers:
MONDO: MONDO:0013674; MedGen: C3280371; Orphanet: 289560; OMIM: 614298

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000045444OMIMno assertion criteria providedPathogenic
(Oct 7, 2011)
germlineliterature only

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

SCV000153733GeneReviewsno assertion criteria providedPathogenic
(Jan 27, 2014)
germlineliterature only

SCV000863972Aziz Sancar Institute of Experimental Medicine,Istanbul Universityno assertion criteria providedPathogenic
(Aug 8, 2018)
germlineclinical testing

SCV000967601Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Likely pathogenic
(Oct 5, 2018)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedliterature only
not providedgermlinenot provided11not providednot providednot providedliterature only, clinical testing
Turkishgermlineyes1not providednot providednot providednot providedclinical testing

Citations

PubMed

Clinical features of neurodegeneration with brain iron accumulation due to a C19orf12 gene mutation.

Goldman JG, Eichenseer SR, Berry-Kravis E, Zimnowodzki S, Gregory A, Hogarth P, Hayflick SJ.

Mov Disord. 2013 Sep;28(10):1462-3. doi: 10.1002/mds.25410. Epub 2013 Mar 13. No abstract available.

PubMed [citation]
PMID:
23494994

Analysis of the C19orf12 and WDR45 genes in patients with neurodegeneration with brain iron accumulation.

Tschentscher A, Dekomien G, Ross S, Cremer K, Kukuk GM, Epplen JT, Hoffjan S.

J Neurol Sci. 2015 Feb 15;349(1-2):105-9. doi: 10.1016/j.jns.2014.12.036. Epub 2015 Jan 3.

PubMed [citation]
PMID:
25592411
See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000045444.5

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

Description

In a Polish patient with neurodegeneration with brain iron accumulation-4 (NBIA4; 614298), Hartig et al. (2011) identified a homozygous c.205G-A transition (c.205G-A, NM_001031726.2) in the C19ORF12 gene, resulting in a gly69-to-arg (G69R) substitution in a highly conserved residue in the transmembrane domain. Another patient was compound heterozygous for G69R and K142E (614297.0004). Neither mutation was found in 750 control chromosomes.

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

From GeneReviews, SCV000153733.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature onlynot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Aziz Sancar Institute of Experimental Medicine,Istanbul University, SCV000863972.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Turkish1not providednot providedclinical testingnot provided

Description

The c.205G>A; p.Gly69Arg (NM_001031726.3) variant is associated with neurodegeneration with brain iron accumulation (Hartig 2011). Our patient had slowly progressive spastic paraparesis without extrapyramidal signs.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000967601.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (6)

Description

The p.Gly69Arg in C19orf12 has been reported in the homozygous or compound heter ozygous state in 6 individuals with mitochondrial membrane protein-associated ne urodegeneration (MPAN; Hartig 2011, Hogarth 2013, Goldman 2013, Tschentscher 201 5). It has also been identified in 7/124358 of European chromosomes by gnomAD (h ttp://gnomad.broadinstitute.org); however, this frequency is low enough to be co nsistent with a recessive carrier frequency. This variant has been reported in C linVar (Variation ID 183298). In vitro functional studies support an impact to p rotein function (Landoure 2013) and computational prediction tools and conservat ion analysis are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive MPA N. ACMG/AMP criteria applied: PM3_Strong, PM2, PP3, PS3_Supporting

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

Last Updated: Sep 12, 2021

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