rs724159990

Variant names:

• chr16-8768220-C-T
• rs724159990
• NM_020686.6:c.631C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_020686.6(ABAT):​c.631C>T​(p.Leu211Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,846 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ABAT NM_020686.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.67
• Publications: 11 publications found

Genes affected

ABAT (HGNC:23): (4-aminobutyrate aminotransferase) 4-aminobutyrate aminotransferase (ABAT) is responsible for catabolism of gamma-aminobutyric acid (GABA), an important, mostly inhibitory neurotransmitter in the central nervous system, into succinic semialdehyde. The active enzyme is a homodimer of 50-kD subunits complexed to pyridoxal-5-phosphate. The protein sequence is over 95% similar to the pig protein. GABA is estimated to be present in nearly one-third of human synapses. ABAT in liver and brain is controlled by 2 codominant alleles with a frequency in a Caucasian population of 0.56 and 0.44. The ABAT deficiency phenotype includes psychomotor retardation, hypotonia, hyperreflexia, lethargy, refractory seizures, and EEG abnormalities. Multiple alternatively spliced transcript variants encoding the same protein isoform have been found for this gene. [provided by RefSeq, Jul 2008]

ABAT Gene-Disease associations (from GenCC):

• GABA aminotransaminase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, Orphanet, G2P
• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898
• PP5: Variant 16-8768220-C-T is Pathogenic according to our data. Variant chr16-8768220-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 162034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABAT	NM_020686.6	c.631C>T	p.Leu211Phe	missense_variant	Exon 10 of 16	ENST00000268251.13	NP_065737.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABAT	ENST00000268251.13	c.631C>T	p.Leu211Phe	missense_variant	Exon 10 of 16	1	NM_020686.6	ENSP00000268251.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461846 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727222

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gamma-aminobutyric acid transaminase deficiency Pathogenic:3

Oct 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 211 of the ABAT protein (p.Leu211Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with GABA-transaminase deficiency (PMID: 25738457, 27903293, 29302074). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 162034). 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 ABAT protein function. Experimental studies have shown that this missense change affects ABAT function (PMID: 25738457, 27903293). 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. -

Jan 01, 2014

Bonnen Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

clinical and in vitro studies -

Feb 01, 2019

Elsea Laboratory, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Aug 09, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.631C>T (p.L211F) alteration is located in exon 10 (coding exon 9) of the ABAT gene. This alteration results from a C to T substitution at nucleotide position 631, causing the leucine (L) at amino acid position 211 to be replaced by a phenylalanine (F). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been identified in the homozygous state in individuals with features consistent with GABA-transaminase deficiency (Besse, 2015; Hu, 2019). This amino acid position is highly conserved in available vertebrate species. In multiple assays testing ABAT function, this variant showed functionally abnormal results (Besse, 2015; Besse, 2016). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.68	D;D;.;D;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	0.99	.;D;D;.;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.4	M;M;.;M;.
PhyloP100		2.7
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.6	D;D;D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D
Polyphen		1.0	D;D;.;D;.
Vest4		0.84
MutPred		0.71		Gain of catalytic residue at L211 (P = 0.0227);Gain of catalytic residue at L211 (P = 0.0227);.;Gain of catalytic residue at L211 (P = 0.0227);Gain of catalytic residue at L211 (P = 0.0227);
MVP		0.91
MPC		1.1
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.89
gMVP		0.89
Mutation Taster		=0/100	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: rs724159990; hg19: chr16-8862077; COSMIC: COSV99190889;