rs121965051

Positions:

• chr10-124403847-G-A
• chr10-124403847-G-C

Variant summary

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

The NM_000274.4(OAT):​c.722C>T​(p.Pro241Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P241P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: OAT NM_000274.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.55

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000274.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 10-124403847-G-A is Pathogenic according to our data. Variant chr10-124403847-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403847-G-A is described in Lovd as [Likely_pathogenic]. Variant chr10-124403847-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OAT	NM_000274.4	c.722C>T	p.Pro241Leu	missense_variant	6/10	ENST00000368845.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OAT	ENST00000368845.6	c.722C>T	p.Pro241Leu	missense_variant	6/10	1	NM_000274.4	P1
OAT	ENST00000539214.5	c.308C>T	p.Pro103Leu	missense_variant	5/9	1
OAT	ENST00000467675.5	n.523C>T		non_coding_transcript_exon_variant	5/7	5
OAT	ENST00000483711.1	n.568C>T		non_coding_transcript_exon_variant	2/2	5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152140 Hom.: 0 Cov.: 32

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251486 Hom.: 0 AF XY: 0.0000441 AC XY: 6 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461840 Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74310

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000268 Hom.: 0

Bravo AF: 0.0000227

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ornithine aminotransferase deficiency Pathogenic:6

Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 28, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 20, 2023	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 241 of the OAT protein (p.Pro241Leu). This variant is present in population databases (rs121965051, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of gyrate atrophy and/or Gyrate atrophy (PMID: 1737786, 28341476; Invitae). ClinVar contains an entry for this variant (Variation ID: 168). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 17, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000168, PMID:1737786). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.9>=0.6). A missense variant is a common mechanism . It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000358). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Dec 21, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with gyrate atrophy of choroid and retina with or without ornithinaemia (MIM#258870). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 9 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated aminotransferase class-III domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been identified in a pair of compound heterozygote siblings with gyrate atrophy (PMID: 11831916) and a homozygote with chorioretinal dystrophy (PMID: 28341476). In addition, it has been classified as likely pathogenic/pathogenic by diagnostic laboratories in ClinVar. (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1992	- -

Hyperornithinemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

May 16, 2023

Variant summary: OAT c.722C>T (p.Pro241Leu) results in a non-conservative amino acid change in 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 3.6e-05 in 251486 control chromosomes (gnomAD). c.722C>T has been reported in the literature as a compound heterozygous genotype in an individual affected with gyrate atrophy and in the homozygous state in an individual affected with chorioretinal dystrophy, both clinical features of Ornithine Aminotransferase Deficiency (Brody_1992, Taylor_2017). These data indicate that the variant may be associated with disease. Furthermore, examination of RNA and protein levels in fibroblasts from the compound heterozygous patient showed normal RNA expression but an undetectable level of protein, suggesting the variant impacts protein stability and/or function (Brody_1992). The following publications have been ascertained in the context of this evaluation (PMID: 1737786, 28341476). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=2)/likely pathogenic (n=1). 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	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-9.8	D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.026	D;D
Sift4G	Uncertain	0.033	D;D
Polyphen		1.0	.;D
Vest4		0.94
MVP		0.98
MPC		0.74
ClinPred		0.86	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.94
gMVP		0.98

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

LitVar

Other links and lift over

dbSNP: rs121965051; hg19: chr10-126092416; COSMIC: COSV100920361; COSMIC: COSV100920361;