rs66724222

Variant names:

• chrX-38408988-G-A
• rs66724222
• NM_000531.6:c.830G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-38408988-G-A
• chrX-38408988-G-T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000531.6(OTC):​c.830G>A​(p.Arg277Gln) variant causes a missense change involving the alteration of a 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R277W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.46
• Publications: 10 publications found

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

ENSG00000250349 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 9 uncertain in NM_000531.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-38408987-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10999.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, 0.993
• PP5: Variant X-38408988-G-A is Pathogenic according to our data. Variant chrX-38408988-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 97339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000531.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTC	NM_000531.6	MANE Select	c.830G>A	p.Arg277Gln	missense	Exon 8 of 10	NP_000522.3
	OTC	NM_001407092.1		c.830G>A	p.Arg277Gln	missense	Exon 10 of 12	NP_001394021.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTC	ENST00000039007.5	TSL:1 MANE Select	c.830G>A	p.Arg277Gln	missense	Exon 8 of 10	ENSP00000039007.4
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-257133G>A		intron	N/A	ENSP00000417050.1
	OTC	ENST00000713758.1		c.830G>A	p.Arg277Gln	missense	Exon 10 of 12	ENSP00000519059.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000182 AC: 2 AN: 1097982 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363358

African (AFR) AF: 0.00 AC: 0 AN: 26395

American (AMR) AF: 0.00 AC: 0 AN: 35201

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19380

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30193

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841914

Other (OTH) AF: 0.00 AC: 0 AN: 46089

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:4

Mar 12, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 23, 2022

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.830G>A (p.Arg277Gln) results in a conservative amino acid change located in the Aspartate/ornithine carbamoyltransferase, Asp/Orn-binding domain 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 183008 control chromosomes. c.830G>A has been reported in the literature in multiple individuals affected with Ornithine Transcarbamylase Deficiency (example Tuchman_1994b, Morizono_1997, Genet_2000, Mak_2007, Storkanova_2013). These data indicate that the variant is likely to be associated with disease. The variant has been reported to negatively impact the stability of the protein in vitro and to reduce its activity to 7% of the wild-type enzyme (Morizono_1997). Three 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 pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Sep 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg277 amino acid residue in OTC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2037279, 2347583, 7860066, 25026867, 30285816). 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. ClinVar contains an entry for this variant (Variation ID: 97339). This missense change has been observed in individuals with OTC deficiency (PMID: 7951259, 17922216). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 277 of the OTC protein (p.Arg277Gln).

Nov 07, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Pathogenic:1

Oct 18, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:1

GenMed Metabolism Lab

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.79
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		9.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.92		Loss of MoRF binding (P = 0.0467)
MVP		1.0
MPC		1.3
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.97
gMVP		0.98
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs66724222; hg19: chrX-38268241;