X-38367331-C-T

Position:

• chrX-38367331-C-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.118C>T​(p.Arg40Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000156 in 1,087,352 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. 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. R40H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000016 (0 hom. 6 hem.)
• Consequence: OTC ENST00000039007.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 4.67

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 7 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-38367332-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant X-38367331-C-T is Pathogenic according to our data. Variant chrX-38367331-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11013.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.118C>T	p.Arg40Cys	missense_variant	2/10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.118C>T	p.Arg40Cys	missense_variant	4/12		NP_001394021.1
OTC	XM_017029556.2	c.118C>T	p.Arg40Cys	missense_variant	2/9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.118C>T	p.Arg40Cys	missense_variant	2/10	1	NM_000531.6	ENSP00000039007	P1
OTC	ENST00000488812.1	n.210C>T		non_coding_transcript_exon_variant	2/6	5
OTC	ENST00000643344.1	c.118C>T	p.Arg40Cys	missense_variant, NMD_transcript_variant	2/11			ENSP00000496606

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.0000109 AC: 2 AN: 183119 Hom.: 0 AF XY: 0.0000148 AC XY: 1 AN XY: 67659

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000156 AC: 17 AN: 1087352 Hom.: 0 Cov.: 27 AF XY: 0.0000170 AC XY: 6 AN XY: 353424

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

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: 0.0000168

Gnomad4 OTH exome AF: 0.0000437

GnomAD4 genome Cov.: 22

Alfa AF: 0.0000688 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 30, 2024	This missense variant replaces arginine with cysteine at codon 40 of the OTC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least three unrelated male individuals affected with late onset ornithine transcarbamylase deficiency (PMID: 7860066, 11260212, 20406775, 27738433; ClinVar Accession: SCV000756189.7). Some of these probands presented with relevant family history: In one family, an affected male carrier's brother died of hyperammonemia and both had minimal residual OTC enzyme activity in his liver. The proband's mother and sister were asymptomatic heterozygous carriers (PMID: 7860066, 11260212). In another family, an affected male carrier's mother who was heterozygous for this variant displayed hyperammonemia after a high-protein meal (PMID: 20406775). This variant has also been reported in the heterozygous state in an unrelated female individual affected with chronic symptoms suggestive of attenuated disease but did not exhibit hyperammonemia (PMID: 37593415). This variant has been identified in 3/204695 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg40His, is reported to cause disease (ClinVar Variation ID: 11014), indicating that arginine at this position is important for OTC protein function. Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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 (OTC) 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 arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (2 heterozygotes, 0 homozygotes, 1 hemizygote). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated aspartate/ornithine carbamoyltransferase, carbamoyl-P binding domain (Pfam). (I) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. p.(Arg40Leu) has previously been reported in an adult male OTC deficiency patient (PMID: 25026867). In addition, p.(Arg40His) has also been reported in at least 10 OTC deficiency patients and has been suggested to result in a milder phenotype then p.(Arg40Cys) (ClinVar, PMID: 25026867; 11260212; 32995020; 19893582). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least eight individuals and is consistently reported as a fatal late childhood/adulthood onset form of ornithine transcarbamylase deficiency (ClinVar; PMID: 7860066; 20406775; 11260212; 27738433). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 27, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 40 of the OTC protein (p.Arg40Cys). This variant is present in population databases (rs72554307, gnomAD 0.003%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with clinical features of ornithine transcarbamylase deficiency (PMID: 7860066, 11260212, 23209112; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11013). 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%. This variant disrupts the p.Arg40 amino acid residue in OTC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7951259, 19893582, 25026867). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 15, 2020	Variant summary: OTC c.118C>T (p.Arg40Cys) results in a non-conservative amino acid change located in the Aspartate/ornithine carbamoyl transferase, carbamoyl-P binding domain (IPR006132) of 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 1.1e-05 in 183119 control chromosomes. c.118C>T has been reported in the literature in individuals affected with later onset Ornithine Transcarbamylase Deficiency and has subsequently cited by others (example, Oppliger Leibundgut_1995, Ploechl_2001, Thurlow_2010, Cavicchi_2014, Caldovic_2015, Ihara_2012). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal OTC activity (Oppliger Leibundgut_1995). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Lastly, another variant at this codon, p.Arg40His has been reported in patients with OTC deficiency supporting the functional relevance of this residue. Based on the evidence outlined above, the variant was classified as pathogenic for fatal late-onset OTC deficiency in boys. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2001	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 24, 2021	The p.Arg40Cys variant in OTC has been previously reported in at least 2 hemizygous males with clinical features of late onset ornithine transcarbamylase (OTC) deficiency (Oppliger Leibundgut 1995 PMID: 7860066, Ploechl 2001 PMID: 11260212, Thurlow 2010 PMID: 20406775). The variant was also identified in one of the affected male's affected sibling and their mother (obligate carrier). Both affected brothers had very minimal to no OTC enzyme activity as measured from liver biopsies (Oppliger Leibundgut 1995 PMID: 7860066, Ploechl 2001 PMID: 11260212). This variant has been reported in ClinVar (Variation ID 11013) and has been identified in 0.003% (3/92405) of European chromosomes by gnomAD, including 1 hemizygote (https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis suggest that this variant may impact the protein. Another variant at the same position, p.Arg40His, has been reported in several probands with features of OTC deficiency is also classified in ClinVar by other clinical laboratories as pathogenic or likely pathogenic (Variation ID 11014). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for X-Linked OTC deficiency. ACMG/AMP criteria applied: PS4_Moderate, PP1, PS3_Supporting, PP3, PM5_Supporting. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	OTC: PM1, PM2, PM5, PP4:Moderate, PS4:Moderate -
Pathogenic, no assertion criteria provided	literature only	GenMed Metabolism Lab	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 13, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23209112, 28324312, 8863155, 9143919, 20406775, 21070677, 11793468, 11260212, 7860066, 8364586, 25026867, 34014569, 35046116) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.48	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0090	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.97		Loss of MoRF binding (P = 0.0367);
MVP		0.93
MPC		1.4
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.71
gMVP		0.97

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: rs72554307; hg19: chrX-38226584;