ClinVar Miner

Submissions for variant NM_001031726.3(C19orf12):c.205G>A (p.Gly69Arg) (rs515726205)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000414809 SCV000492735 pathogenic Dystonia; Mental deterioration; Tremor; Adult-onset night blindness; Peripheral visual field loss 2015-07-01 criteria provided, single submitter clinical testing
Invitae RCV000528859 SCV000647089 pathogenic Spastic paraplegia 43, autosomal recessive 2020-02-20 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 69 of the C19orf12 protein (p.Gly69Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs515726205, ExAC 0.005%). This variant has been observed to be homozygous or in combination with another C19orf12 variant in several individuals affected with neurodegeneration with brain iron accumulation (NBIA) (PMID: 21981780, 23269600, 23494994, 25592411, 30088953). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 31157). Experimental evidence suggests that this variant results in altered protein localization compared to wild-type protein (PMID: 23857908). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000024153 SCV000967601 likely pathogenic Neurodegeneration with brain iron accumulation 4 2018-10-05 criteria provided, single submitter clinical testing 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
OMIM RCV000024153 SCV000045444 pathogenic Neurodegeneration with brain iron accumulation 4 2011-10-07 no assertion criteria provided literature only
GeneReviews RCV000024153 SCV000153733 pathogenic Neurodegeneration with brain iron accumulation 4 2014-01-27 no assertion criteria provided literature only
Aziz Sancar Institute of Experimental Medicine,Istanbul University RCV000024153 SCV000863972 pathogenic Neurodegeneration with brain iron accumulation 4 2018-08-08 no assertion criteria provided clinical testing 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.

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