X-38403699-G-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 10P and 4B. PM1PM5PP2PP3_StrongPP5BS2

The NM_000531.6(OTC):c.622G>T(p.Ala208Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00001 in 1,096,509 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A208T) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.000010 ( 0 hom. 5 hem. )

Consequence

OTC
NM_000531.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3

Conservation

PhyloP100: 6.31

Publications

18 publications found

Variant links:

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]

OTC Gene-Disease associations (from GenCC):

ornithine carbamoyltransferase deficiency
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Laboratory for Molecular Medicine, Orphanet

OTC links:

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 28 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000531.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-38403699-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 97274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 266 curated pathogenic missense variants (we use a threshold of 10). The gene has 15 curated benign missense variants. Gene score misZ: 1.3274 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to ornithine carbamoyltransferase deficiency.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.966

PP5

Variant X-38403699-G-T is Pathogenic according to our data. Variant chrX-38403699-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2083011.

BS2

High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
OTC	NM_000531.6 link	c.622G>T	p.Ala208Ser	missense_variant	Exon 6 of 10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1 link	c.622G>T	p.Ala208Ser	missense_variant	Exon 8 of 12		NP_001394021.1
OTC	XM_017029556.2 link	c.622G>T	p.Ala208Ser	missense_variant	Exon 6 of 9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5 link	c.622G>T	p.Ala208Ser	missense_variant	Exon 6 of 10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1 link	c.172-262422G>T		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000546

AC:

AN:

183108

AF XY:

0.00

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000100

AC:

AN:

1096509

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

361933

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26355

American (AMR)

AF:

0.00

AC:

AN:

35200

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19368

East Asian (EAS)

AF:

0.00

AC:

AN:

30193

South Asian (SAS)

AF:

0.00

AC:

AN:

54110

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40522

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4129

European-Non Finnish (NFE)

AF:

0.0000131

AC:

AN:

840595

Other (OTH)

AF:

0.00

AC:

AN:

46037

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ornithine carbamoyltransferase deficiency

Pathogenic:1Uncertain:1

Apr 11, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ala208 amino acid residue in OTC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9007316, 9028466, 10799432, 25949836, 26819360). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has not been reported in the literature in individuals affected with OTC-related conditions. This variant is present in population databases (rs72558416, gnomAD 0.001%). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 208 of the OTC protein (p.Ala208Ser). -

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Dec 22, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25026867, 9007316, 17437397) -

not specified

Uncertain:1

Jun 27, 2025

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: OTC c.622G>T (p.Ala208Ser) results in a conservative amino acid change located in the Aspartate/ornithine carbamoyltransferase, Asp/Orn-binding domain (IPR006131) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 5.5e-06 in 183108 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.622G>T in individuals affected with Ornithine Transcarbamylase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. A different variant affecting the same codon has been classified as pathogenic by our lab (c.622G>A, p.Ala208Thr), supporting the critical relevance of codon 208 to OTC protein function. ClinVar contains an entry for this variant (Variation ID: 2083011). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Jan 28, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.622G>T (p.A208S) alteration is located in exon 6 (coding exon 6) of the OTC gene. This alteration results from a G to T substitution at nucleotide position 622, causing the alanine (A) at amino acid position 208 to be replaced by a serine (S). Based on data from gnomAD, the T allele has an overall frequency of 0.0011% (1/183108) total alleles studied, with 0 hemizygote(s) observed. The highest observed frequency was 0.0025% (1/40809) of non-Finnish European alleles. Other variant(s) at the same codon, c.622G>A (p.A208T), have been identified in individual(s) with features consistent with ornithine transcarbamylase deficiency (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 insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.9

PhyloP100

6.3

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.9

REVEL

Pathogenic

0.78

Sift

Benign

0.10

Sift4G

Benign

0.089

Polyphen

0.96

Vest4

0.70

MutPred

0.86

Gain of disorder (P = 0.0399);

MVP

0.96

MPC

1.1

ClinPred

0.72

GERP RS

5.9

Varity_R

0.65

gMVP

0.85

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over