NM_000531.6:c.119G>A

Variant names:

• chrX-38367332-G-A
• rs72554308
• NM_000531.6:c.119G>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000531.6(OTC):​c.119G>A​(p.Arg40His) 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 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/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 5.09

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]

ENSG00000250349 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant X-38367332-G-A is Pathogenic according to our data. 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. Variant chrX-38367332-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6	c.119G>A	p.Arg40His	missense_variant	Exon 2 of 10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.119G>A	p.Arg40His	missense_variant	Exon 4 of 12		NP_001394021.1
OTC	XM_017029556.2	c.119G>A	p.Arg40His	missense_variant	Exon 2 of 9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.119G>A	p.Arg40His	missense_variant	Exon 2 of 10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-298789G>A		intron_variant	Intron 3 of 8	5		ENSP00000417050.1
OTC	ENST00000488812.1	n.211G>A		non_coding_transcript_exon_variant	Exon 2 of 6	5
OTC	ENST00000643344.1	n.119G>A		non_coding_transcript_exon_variant	Exon 2 of 11			ENSP00000496606.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1087008 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 353122

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/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:10

May 10, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 30, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 21, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 disease. (I) 0115 - Variants in this gene are known to have variable expressivity. In males, the phenotypic spectrum can range from lethal neonatal onset to milder forms in late childhood or adulthood while in heterozygous females, the phenotypic spectrum can range from asymptomatic to having recurrent hyperammonemia and/or neurologic impairment depending on the pattern of X-chromosome inactivation in the liver (OMIM, GeneReviews). In addition, individuals with pathogenic variants associated with mild, late-onset disease may experience severe hyperammonemia depending on exposure to strong environmental stressors (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (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) (p.(Arg40Cys): 2 heterozygotes, 1 hemizygote, 0 homozygote). (I) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0600 - Variant is located in the annotated OTCace_N domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical diagnostic laboratories (ClinVar). While this variant is commonly associated with milder, later-onset ornithine transcarbamylase deficiency, it has been reported in the context of severe early-onset disease, including one 7-day-old infant (PMIDs: 19893582, 25958381, 32934962). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

May 29, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: OTC c.119G>A (p.Arg40His) 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 183119 control chromosomes (gnomAD). c.119G>A has been reported in the literature in multiple individuals affected with ornithine transcarbamylase deficiency and several of these individuals had a late-onset presentation (example: Toquet_2020 , Harada_2006 ). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.118C>T, p.Arg40Cys), supporting the critical relevance of codon 40 to OTC protein function. In vitro and in vivo functional studies reveal reduced activity of the variant (Augustin_2000, Harada_2006). The following publications have been ascertained in the context of this evaluation (PMID: 34014557, 16635166, 11102556). ClinVar contains an entry for this variant (Variation ID: 11014). Based on the evidence outlined above, the variant was classified as pathogenic. -

May 25, 2017

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.119G>A (p.Arg40His) variant was previously detected in several patients and families with OTC deficiency, males and females [PMID 21070677, 2095337, 7951259]. Among them, a heterozygous female became symptomatic with hyperammenomia and acute decompensation at 13 years of age [PMID 21070677]. Additionally, a family with a hemizygous male and heterozygous sister also became symptomatic in their teenage years [PMID 2095337]. Their mother, also heterozygous, was asymptomatic but showed small orotic aciduria after protein loading. This variant has also been observed in our internal database in a 10 y/o patient with recent symptoms of OTC deficiency. Another change at the same amino acid location (p.Arg40Cys) has been reported but is considered a variant of unknown significance by our classification criteria at this time. This variant is not conserved in all mammals. Computer based prediction softwares yield discordant results regarding the pathogenicity of this change. This variant has not been observed in the ExAC database but has been detected in multiple patients and it is thus classified as pathogenic. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 40 of the OTC protein (p.Arg40His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ornithine transcarbamylase deficiency (PMID: 7951259, 19893582, 25026867). ClinVar contains an entry for this variant (Variation ID: 11014). 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%. Experimental studies have shown that this missense change affects OTC function (PMID: 11102556). 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: 7860066, 7951259, 19893582, 23209112, 25026867; Invitae). 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. -

Jul 15, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:5

Sep 07, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PP4, PM2, PM5, PS3 -

Dec 07, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 07, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); 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: 9175746, 34014569, 32995020, 32934962, 7951259, 30449781, 28324312, 31447099, 21070677, 33309754, 33272297, 33763331, 36854409, 19893582, 37146589, 17334707, 11260212, 11768581, 8863155, 11102556, 34014557, 9048915, 25026867) -

May 03, 2023

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PP3, PM2_SUP -

-

GenMed Metabolism Lab

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.85	D
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.022	D
Polyphen		0.54	P
Vest4		0.77
MutPred		0.98		Loss of MoRF binding (P = 0.0407);
MVP		0.91
MPC		0.61
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.54
gMVP		0.94

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: rs72554308; hg19: chrX-38226585;