NM_000274.4:c.583G>T

Variant names:

• chr10-124405501-C-A
• rs386833614
• NM_000274.4:c.583G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_000274.4(OAT):​c.583G>T​(p.Asp195Tyr) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D195N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OAT NM_000274.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.48
• Publications: 3 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 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: MetaRNN computational evidence supports a deleterious effect, 0.893
• PP5: Variant 10-124405501-C-A is Pathogenic according to our data. Variant chr10-124405501-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 56132.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OAT	NM_000274.4	c.583G>T	p.Asp195Tyr	missense_variant	Exon 5 of 10	ENST00000368845.6	NP_000265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OAT	ENST00000368845.6	c.583G>T	p.Asp195Tyr	missense_variant	Exon 5 of 10	1	NM_000274.4	ENSP00000357838.5
OAT	ENST00000539214.5	c.169G>T	p.Asp57Tyr	missense_variant	Exon 4 of 9	1		ENSP00000439042.1
OAT	ENST00000467675.5	n.384G>T		non_coding_transcript_exon_variant	Exon 4 of 7	5
OAT	ENST00000483711.1	n.429G>T		non_coding_transcript_exon_variant	Exon 1 of 2	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ornithine aminotransferase deficiency Pathogenic:1 Uncertain:1

Dec 20, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 195 of the OAT protein (p.Asp195Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with gyrate atrophy (PMID: 8670789). ClinVar contains an entry for this variant (Variation ID: 56132). 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 not expected to disrupt OAT protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hyperornithinemia Pathogenic:1

Jan 28, 2025

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: OAT c.583G>T (p.Asp195Tyr) results in a non-conservative amino acid change located in the PLP-dependent transferases domain (IPR015424) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251464 control chromosomes. c.583G>T has been reported in the literature in at-least one individual affected with Ornithine Aminotransferase Deficiency with undetectable Ornithine ketoacid aminotransferase activity in vitro in PHA-transformed lymphocytes and cultured skinfibroblasts (example: Mashima_1996). The following publications have been ascertained in the context of this evaluation (PMID: 8670789, 7260021). ClinVar contains an entry for this variant (Variation ID: 56132). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.85	.;D
Eigen	Benign	-0.065
Eigen_PC	Benign	0.082
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.0	.;L
PhyloP100		7.5
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Pathogenic	0.71
Sift	Benign	0.057	T;D
Sift4G	Benign	0.067	T;T
Polyphen		0.046	.;B
Vest4		0.81
MutPred		0.81		.;Loss of disorder (P = 0.0247);
MVP		0.87
MPC		0.68
ClinPred		0.92	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.65
gMVP		0.90
Mutation Taster		=56/44	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs386833614; hg19: chr10-126094070;