NM_000274.4:c.1205T>C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B.

PM2PP2PP3PP5_Very_StrongBP4

The NM_000274.4(OAT):c.1205T>C(p.Leu402Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,614,158 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00020 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

OAT
NM_000274.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 8.86

Publications

15 publications found

Variant links:

Genes affected

OAT (HGNC:8091): (ornithine aminotransferase) This gene encodes the mitochondrial enzyme ornithine aminotransferase, which is a key enzyme in the pathway that converts arginine and ornithine into the major excitatory and inhibitory neurotransmitters glutamate and GABA. Mutations that result in a deficiency of this enzyme cause the autosomal recessive eye disease Gyrate Atrophy. Alternatively spliced transcript variants encoding different isoforms have been described. Related pseudogenes have been defined on the X chromosome. [provided by RefSeq, Jan 2010]

OAT Gene-Disease associations (from GenCC):

ornithine aminotransferase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet

OAT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 35 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.87566 (below the threshold of 3.09). Trascript score misZ: 1.6556 (below the threshold of 3.09). GenCC associations: The gene is linked to ornithine aminotransferase deficiency.

PP3

Multiple lines of computational evidence support a deleterious effect 12: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 10-124398057-A-G is Pathogenic according to our data. Variant chr10-124398057-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.41031438). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OAT	NM_000274.4 link	c.1205T>C	p.Leu402Pro	missense_variant	Exon 10 of 10	ENST00000368845.6	NP_000265.1	P04181-1A0A140VJQ4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OAT	ENST00000368845.6 link	c.1205T>C	p.Leu402Pro	missense_variant	Exon 10 of 10	1	NM_000274.4	ENSP00000357838.5	P04181-1
OAT	ENST00000539214.5 link	c.791T>C	p.Leu264Pro	missense_variant	Exon 9 of 9	1		ENSP00000439042.1	P04181-2
OAT	ENST00000471127.1 link	n.715T>C		non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00264

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000271

AC:

AN:

251176

AF XY:

0.000302

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:

0.00282

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000102

AC:

149

AN:

1461818

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00255

AC:

136

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000809

AC:

AN:

1111968

Other (OTH)

AF:

0.0000662

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

AF:

0.000197

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41584

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00264

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.0000247

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.000255

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ornithine aminotransferase deficiency

Pathogenic:3

Feb 28, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2018

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 26, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 OAT protein function. ClinVar contains an entry for this variant (Variation ID: 156). This missense change has been observed in individuals with OAT-related conditions (PMID: 1737786, 2492100). It is commonly reported in individuals of Finnish ancestry (PMID: 1737786, 2492100). This variant is present in population databases (rs121965043, gnomAD 0.3%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 402 of the OAT protein (p.Leu402Pro). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects OAT function (PMID: 1737786, 2492100). -

Hyperornithinemia

Pathogenic:1

Dec 13, 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: OAT c.1205T>C (p.Leu402Pro) results in a non-conservative amino acid change at a highly conserved amino acid residue (Brody_1992) 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 0.00027 in 251176 control chromosomes. This frequency is not higher than the estimated maximum expected for a pathogenic variant in OAT causing Ornithine Aminotransferase Deficiency (0.00027 vs 0.0011), allowing no conclusion about variant significance. The variant, c.1205T>C, has been reported in the literature in many homozygous-, as well as compound heterozygous individuals affected with Gyrate atrophy, including multiple evidence for cosegregation (Mitchell_1989, Peltola_2002); the variant is reported as a known Finnish founder mutation in the literature (Peltola_2002). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, showing a substantial reduction in OAT protein expression and a loss of enzymatic activity (Mitchell_1989, Brody_1992). Two submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

.;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.62

MetaRNN

Benign

0.41

T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.8

.;H

PhyloP100

8.9

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-6.8

D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.98

MVP

0.99

MPC

1.1

ClinPred

0.65

GERP RS

5.1

Varity_R

0.99

gMVP

0.99

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over