rs768219929

chr6-24503413-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_001080.3(ALDH5A1):c.589G>A(p.Val197Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000639 in 1,613,018 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000067 (0 hom.)
• Consequence: ALDH5A1 NM_001080.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:7
• Conservation: PhyloP100: 9.59

Genes affected

ALDH5A1 (HGNC:408): (aldehyde dehydrogenase 5 family member A1) This protein belongs to the aldehyde dehydrogenase family of proteins. This gene encodes a mitochondrial NAD(+)-dependent succinic semialdehyde dehydrogenase. A deficiency of this enzyme, known as 4-hydroxybutyricaciduria, is a rare inborn error in the metabolism of the neurotransmitter 4-aminobutyric acid (GABA). In response to the defect, physiologic fluids from patients accumulate GHB, a compound with numerous neuromodulatory properties. Two transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001080.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH5A1	NM_001080.3	c.589G>A	p.Val197Met	missense_variant	3/10	ENST00000357578.8
ALDH5A1	NM_170740.1	c.589G>A	p.Val197Met	missense_variant	3/11
ALDH5A1	NM_001368954.1	c.589G>A	p.Val197Met	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH5A1	ENST00000357578.8	c.589G>A	p.Val197Met	missense_variant	3/10	1	NM_001080.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000440 AC: 11 AN: 250134 Hom.: 0 AF XY: 0.0000517 AC XY: 7 AN XY: 135298

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000671 AC: 98 AN: 1460796 Hom.: 0 Cov.: 33 AF XY: 0.0000647 AC XY: 47 AN XY: 726734

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000612

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74362

Gnomad4 AFR AF: 0.0000724

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: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000906 Hom.: 0

Bravo AF: 0.000117

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Succinate-semialdehyde dehydrogenase deficiency Pathogenic:1 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 10, 2016	The ALDH5A1 c.589G>A (p.Val197Met) variant is a missense variant that has been reported in a compound heterozgyous state with a second missense variant in a child with succinic semialdehyde dehydrogenase (SSADH) deficiency (Liu et al. 2014). Family studies revealed that the child inherited the p.Val197Met variant from his mother and the second missense variant from his father. The p.Val197Met variant was absent from 100 healthy ethnically matched control individuals and is reported at a frequency of 0.000196 in the African population of the Exome Aggregation Consortium. This frequency is based on two alleles in a region of good sequencing coverage, so the variant is presumed to be rare. The evidence for this variant is limited. The p.Val197Met variant is thus classified as a variant of unknown significance but suspicious for pathogenicity for succinic semialdehyde dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 05, 2022	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 197 of the ALDH5A1 protein (p.Val197Met). This variant is present in population databases (rs768219929, gnomAD 0.01%). This missense change has been observed in individual(s) with succinic semialdehyde dehydrogenase (PMID: 25431891). ClinVar contains an entry for this variant (Variation ID: 356132). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ALDH5A1 protein function. 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. -
Likely pathogenic, criteria provided, single submitter	curation	Elsea Laboratory, Baylor College of Medicine	Mar 08, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 05, 2020	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 14, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ALDH5A1 p.Val197Met variant was identified in dbSNP (ID: rs768219929) as "With Uncertain significance allele" and in Clinvar (classified as VUS by Ambry Genetics, Illumina Clinical Services, and EGL Diagnostics with the associated conditions of Succinate-semialdehyde dehydrogenase deficiency and inborn genetic diseases). The variant was not identified in Cosmic and LOVD 3.0 databases. The variant was also found in control databases in 12 of 281530 chromosomes at a frequency of 0.000043 (Genome Aggregation Database Feb 27, 2017), in the following populations: Latino in 5 of 35406 chromosomes (freq: 0.000141), Other in 1 of 7202 chromosomes (freq: 0.000139), African in 2 of 24914 chromosomes (freq: 0.00008) and European (non-Finnish) in 4 of 128826 chromosomes (freq: 0.000031), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish) and South Asian populations. In a case study, genetic analysis of ALDH5A1 was performed for a male child with SSADH deficiency, his parents, and their 10 weeks' gestation at-risk fetus as well as 100 healthy unrelated volunteers. The proband was identified to have compound heterozygous mutations c.496T>C (p.W166R) and c.589G>A (p.V197M). Each of his parents carried a mutation. DNA sequencing of chorionic villus revealed the fetus was a carrier and this was confirmed after birth by genetic analysis of umbilical cord blood and urine organic acid analysis (Liu_2016_PMID: 25431891). The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder) predict a greater than 10% difference in splicing (gain of a 5' splice site at c.586). The p.Val197 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 15, 2024

Variant summary: ALDH5A1 c.589G>A (p.Val197Met) results in a conservative amino acid change located in the Aldehyde dehydrogenase domain (IPR015590) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 250134 control chromosomes. c.589G>A has been reported in the literature in trans along with an apparently VUS missense in an individual affected with Succinic Semialdehyde Dehydrogenase Deficiency (Liu_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Succinic Semialdehyde Dehydrogenase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 25431891).ClinVar contains an entry for this variant (Variation ID: 356132). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	H;.;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.92
MVP		0.99
MPC		0.94
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.96

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: rs768219929; hg19: chr6-24503641; COSMIC: COSV62374751;