rs72558416
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_000531.6(OTC):c.622G>A(p.Ala208Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,096,505 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A208S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000531.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTC | NM_000531.6 | c.622G>A | p.Ala208Thr | missense_variant | 6/10 | ENST00000039007.5 | |
OTC | NM_001407092.1 | c.622G>A | p.Ala208Thr | missense_variant | 8/12 | ||
OTC | XM_017029556.2 | c.622G>A | p.Ala208Thr | missense_variant | 6/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTC | ENST00000039007.5 | c.622G>A | p.Ala208Thr | missense_variant | 6/10 | 1 | NM_000531.6 | P1 | |
OTC | ENST00000643344.1 | c.*372G>A | 3_prime_UTR_variant, NMD_transcript_variant | 7/11 | |||||
OTC | ENST00000488812.1 | downstream_gene_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD4 exome AF: 0.00000821 AC: 9AN: 1096505Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 5AN XY: 361931
GnomAD4 genome ? Cov.: 23
ClinVar
Submissions by phenotype
Ornithine carbamoyltransferase deficiency Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 07, 2020 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jun 24, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ornithine transcarbamylase deficiency (MIM#311250). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a minor amino acid change. (SP) 0600 - Variant is located in the annotated Aspartate/ornithine carbamoyltransferase, Asp/Orn binding domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individual and has been reported more than five times as pathogenic in ClinVar. In the literature, this variant is well-reported in patients with ornithine transcarbamylase deficiency and is typically asscoiated with late-onset disease. However, it has also been reported to cause severe disease in childhood (LOVD, PMID: 9007316, 28261508, 34014557). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 12, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 208 of the OTC protein (p.Ala208Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ornithine transcarbamylase deficiency (PMID: 9007316, 9028466, 10799432, 25949836, 26819360). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 97274). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt OTC protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:4
Pathogenic, no assertion criteria provided | literature only | GenMed Metabolism Lab | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 28, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18071043, 34014569, 34014557, 25026867, 26819360, 28261508, 17437397, 9028466, 28597413, 28324312, 33309754, 33272297, 9007316) - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 17, 2023 | The c.622G>A (p.A208T) alteration is located in exon 6 (coding exon 6) of the OTC gene. This alteration results from a G to A substitution at nucleotide position 622, causing the alanine (A) at amino acid position 208 to be replaced by a threonine (T). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple individuals with ornithine transcarbamylase deficiency and segregates with disease in multiple families (van Diggelen, 1996; Schultz, 2000; Cavicchi, 2014; Martín-Hernández, 2014; Gascon-Bayarri, 2015; Sánchez, 2017; Silvera-Ruiz, 2019; Lu, 2020). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at