chr19-29702966-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_031448.6(C19orf12):c.172G>A(p.Gly58Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G58S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_031448.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152082Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000241 AC: 6AN: 249134Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 134862
GnomAD4 exome AF: 0.0000192 AC: 28AN: 1461626Hom.: 0 Cov.: 37 AF XY: 0.0000151 AC XY: 11AN XY: 727122
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152082Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74288
ClinVar
Submissions by phenotype
Neurodegeneration with brain iron accumulation 4 Pathogenic:4
ACMG classification criteria: PS4 moderate, PM2, PM3, PP3 -
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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. -
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 -
not provided Pathogenic:2
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C19orf12: PM3:Very Strong, PM2, PP3 -
Neurodegeneration with brain iron accumulation Pathogenic:1
Variant summary: C19orf12 c.172G>A (p.Gly58Arg), also referred to as c.205G>A (p.Gly69Arg), results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 249134 control chromosomes (gnomAD). c.172G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Neurodegeneration With Brain Iron Accumulation (e.g. Hartig_2011, Hogarth_2013, Tschentscher_2015). These data indicate that the variant is very likely to be associated with disease. Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=4)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -
Hereditary spastic paraplegia 43 Pathogenic:1
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 69 of the C19orf12 protein (p.Gly69Arg). This variant is present in population databases (rs515726205, gnomAD 0.006%). This missense change has been observed in individual(s) with neurodegeneration with brain iron accumulation (NBIA) (PMID: 21981780, 23269600, 23494994, 25592411, 30088953). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 31157). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects C19orf12 function (PMID: 23857908). For these reasons, this variant has been classified as Pathogenic. -
Hereditary spastic paraplegia 43;C3280371:Neurodegeneration with brain iron accumulation 4 Pathogenic:1
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Dystonic disorder;C0040822:Tremor;C0234985:Mental deterioration;C0241688:Peripheral visual field loss;C4024790:Adult-onset night blindness Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at