rs72558416

Positions:

• chrX-38403699-G-A
• chrX-38403699-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The ENST00000039007.5(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:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000082 (0 hom. 5 hem.)
• Consequence: OTC ENST00000039007.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 6.31

Genes affected

OTC (HGNC:8512): (ornithine transcarbamylase) This nuclear gene encodes a mitochondrial matrix enzyme. The encoded protein is involved in the urea cycle which functions to detoxify ammonia into urea for excretion. Mutations in this enzyme lead to ornithine transcarbamylase deficiency, which causes hyperammonemia. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in ENST00000039007.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-38403699-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2083011.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant X-38403699-G-A is Pathogenic according to our data. Variant chrX-38403699-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 97274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38403699-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTC	NM_000531.6	c.622G>A	p.Ala208Thr	missense_variant	6/10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.622G>A	p.Ala208Thr	missense_variant	8/12		NP_001394021.1
OTC	XM_017029556.2	c.622G>A	p.Ala208Thr	missense_variant	6/9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.622G>A	p.Ala208Thr	missense_variant	6/10	1	NM_000531.6	ENSP00000039007	P1
OTC	ENST00000643344.1	c.*372G>A		3_prime_UTR_variant, NMD_transcript_variant	7/11			ENSP00000496606
OTC	ENST00000488812.1			downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000821 AC: 9 AN: 1096505 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 5 AN XY: 361931

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000107

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Aug 01, 2024	ACMG Criteria: PS4, PM1, PM2_P, PP1, PP3, PP5; Variant was found in hemizygous state -
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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 15, 2024	Variant summary: OTC c.622G>A (p.Ala208Thr) results in a non-conservative amino acid change located in the Aspartate/ornithine carbamoyltransferase, Asp/Orn-binding domain (IPR006131) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183108 control chromosomes. c.622G>A has been reported in the literature in multiple individuals affected with late-onset Ornithine Transcarbamylase Deficiency (e.g. Toquet_2021, van Diggelen_1996, Ausems_1997). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 9028466, 34014557, 9007316). ClinVar contains an entry for this variant (Variation ID: 97274). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	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	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	literature only	GenMed Metabolism Lab	-	- -
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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.70
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.90		Gain of ubiquitination at K210 (P = 0.1621);
MVP		1.0
MPC		1.1
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.85
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs72558416; hg19: chrX-38262952; COSMIC: COSV50001314; COSMIC: COSV50001314;