rs72558462

Positions:

• chrX-38411897-A-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000531.6(OTC):​c.903A>T​(p.Leu301Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.74

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 0 benign, 4 uncertain in NM_000531.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant X-38411897-A-T is Pathogenic according to our data. Variant chrX-38411897-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 97350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTC	NM_000531.6	c.903A>T	p.Leu301Phe	missense_variant	9/10	ENST00000039007.5
OTC	NM_001407092.1	c.903A>T	p.Leu301Phe	missense_variant	11/12
OTC	XM_017029556.2			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTC	ENST00000039007.5	c.903A>T	p.Leu301Phe	missense_variant	9/10	1	NM_000531.6	P1
OTC	ENST00000643344.1	c.*653A>T		3_prime_UTR_variant, NMD_transcript_variant	10/11

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 20, 2023	Variant summary: OTC c.903A>T (p.Leu301Phe) 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 183317 control chromosomes (gnomAD and publication data). c.903A>T has been reported in the literature in hemizygous individuals affected with Ornithine Transcarbamylase Deficiency (e.g. Climent_2002, Morel_2012, Lung_2022). In addition, at least one publication reports the residual OTC activity in the liver of a hemizygous patient as 3% of normal activity (e.g. Climent_2002). These data indicate that the variant is likely associated with disease. Furthermore, a different variant resulting in the same amino acid change (c.903A>C, p.Leu301Phe) has been reported in a male proband with OTD deficiency whose mother was a carrier and his maternal uncle and brother were both affected (Barbosa-Gouveia_2021), providing supporting evidence for a pathogenic role. The following publications have been ascertained in the context of this evaluation (PMID: 11793483, 35949797, 28324312, 22340867, 34440436). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 24, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 18, 2022	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 301 of the OTC protein (p.Leu301Phe). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu301 amino acid residue in OTC. Other variant(s) that disrupt this residue have been observed in individuals with OTC-related conditions (PMID: 26059767), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. ClinVar contains an entry for this variant (Variation ID: 97350). This missense change has been observed in individual(s) with ornithine transcarbamylase deficiency (PMID: 11793483, 22340867; Invitae). -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 15, 2021	The OTC c.903A>T; p.Leu301Phe variant (rs72558462) is reported in the literature in multiple individuals affected with ornithine transcarbamylase deficiency (Climent 2002, Morel 2012). Functional analyses of the variant protein show residual liver OTC activity of 3% (Capistrano-Estrada 1994, Climent 2002). This variant is also reported in ClinVar (Variation ID: 97350). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, another variant at this codon (c.902T>C, p.Leu301Ser) has been reported in an individual with OTC deficiency and is considered disease causing (Caldovic 2015). The leucine at codon 301 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.86). Based on available information, this variant is considered to be likely pathogenic. References: Caldovic L et al. Genotype-Phenotype Correlations in Ornithine Transcarbamylase Deficiency: A Mutation Update. J Genet Genomics. 2015 May 20;42(5):181-94. PMID: 26059767. Capistrano-Estrada S et al. Histopathological findings in a male with late-onset ornithine transcarbamylase deficiency. Pediatr Pathol. 1994 Mar-Apr;14(2):235-43. PMID: 8008687. Climent C et al. Identification of seven novel missense mutations, two splice-site mutations, two microdeletions and a polymorphic amino acid substitution in the gene for ornithine transcarbamylase (OTC) in patients with OTC deficiency. Hum Mutat. 2002 Feb;19(2):185-6. PMID: 11793483. Morel N et al. Diagnosis of ornithine transcarbamylase deficiency secondary to p.Leu301Phe mutation in an adult patient. Rev Neurol (Paris). 2012 Mar;168(3):296-7. PMID: 22340867. -

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

GenMed Metabolism Lab

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.66	D
BayesDel_noAF	Pathogenic	0.70
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.95		Loss of sheet (P = 0.1398);
MVP		1.0
MPC		1.2
ClinPred		0.99	D
GERP RS		1.3
Varity_R		0.94
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.36		Position offset: 15
DS_AL_spliceai		0.23		Position offset: -35

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

Publications

LitVar

Other links and lift over

dbSNP: rs72558462; hg19: chrX-38271150;