rs1555198495
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_000317.3(PTS):āc.340A>Gā(p.Ile114Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,194 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000317.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461194Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726822
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
6-Pyruvoyl-tetrahydrobiopterin synthase deficiency Pathogenic:2Uncertain:3
The PTS c.340A>G (p.Ile114Val) missense variant has been reported in at least one study in which it is identified in a single individual from a consanguineous family who presented with a wide array of phenotypes some of which include seizures, lower limb spasticity, intellectual disability, and fluctuations in motor ability. The variant was detected in a homozygous state in this individual and in a heterozygous state in two unaffected family members (Hanihara et al. 1997). The p.Ile114Val variant was absent from 50 controls and is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium or the Genome Aggregation Database. Based on the evidence, the p.Ile114Val variant is classified as a variant of unknown significance but suspicious for pathogenicity for 6-pyruvoyltetrahydropterin synthase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
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Variant summary: PTS c.340A>G (p.Ile114Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250116 control chromosomes (gnomAD). c.340A>G has been reported in the literature in homozygous individuals affected with 6-Pyruvoyl-Tetrahydropterin Synthase Deficiency, one of which had a milder form of the disease (Ashida_1994, Hanihara_1997). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 7698774, 9159737). ClinVar contains an entry for this variant (Variation ID: 558723). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at