X-38408752-C-T

Position:

• chrX-38408752-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000531.6(OTC):​c.674C>T​(p.Pro225Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. P225R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.28

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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant X-38408752-C-T is Pathogenic according to our data. Variant chrX-38408752-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTC	NM_000531.6	c.674C>T	p.Pro225Leu	missense_variant	7/10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.674C>T	p.Pro225Leu	missense_variant	9/12		NP_001394021.1
OTC	XM_017029556.2	c.674C>T	p.Pro225Leu	missense_variant	7/9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.674C>T	p.Pro225Leu	missense_variant	7/10	1	NM_000531.6	ENSP00000039007	P1
OTC	ENST00000643344.1	c.*424C>T		3_prime_UTR_variant, NMD_transcript_variant	8/11			ENSP00000496606

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1084891 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 351745

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1991	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 09, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 29, 2019	Variant summary: OTC c.674C>T (p.Pro225Leu) results in a non-conservative amino acid change located in the Aspartate/ornithine carbamoyltransferase, Asp/Orn-binding domain (IPR006131) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182904 control chromosomes (gnomAD). The variant, c.674C>T, has been reported in the literature in multiple individuals affected with Ornithine Transcarbamylase Deficiency (OTCD) (Hentzen_1991, Garcia-Perez_1997, Matsuda_1997, McCullough_2000, Bijarnia-Mahay_2018). Hentzen_1991 reported this variant to segregate with OTCD in one family. These data indicate that the variant is very likely to be associated with disease. Several publications also reported (near) undetectable residual enzyme activities from patient samples (Hentzen_1991, Garcia-Perez_1997, Matsuda_1997, McCullough_2000). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic (1x) or pathogenic (2x). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 01, 2022	This missense change has been observed in individuals with ornithine transcarbamylase (OTC) deficiency (PMID: 1721894, 9286441, 9427144, 27070778). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 225 of the OTC protein (p.Pro225Leu). ClinVar contains an entry for this variant (Variation ID: 11000). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro225 amino acid residue in OTC. Other variant(s) that disrupt this residue have been observed in individuals with OTC-related conditions (PMID: 9427144, 10946359, 19669271), which suggests that this may be a clinically significant amino acid residue. 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. -

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	GenMed Metabolism Lab	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.64
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.95	D
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.93
Sift	Benign	0.72	T
Sift4G	Benign	0.36	T
Polyphen		1.0	D
Vest4		0.87
MutPred		0.93		Loss of disorder (P = 0.0358);
MVP		0.99
MPC		1.2
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.83
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs67120076; hg19: chrX-38268005; COSMIC: COSV99234000;