rs864321670

Positions:

• chr10-95633012-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_002860.4(ALDH18A1):​c.755G>A​(p.Arg252Gln) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R252G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALDH18A1 NM_002860.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.46

Genes affected

ALDH18A1 (HGNC:9722): (aldehyde dehydrogenase 18 family member A1) This gene is a member of the aldehyde dehydrogenase family and encodes a bifunctional ATP- and NADPH-dependent mitochondrial enzyme with both gamma-glutamyl kinase and gamma-glutamyl phosphate reductase activities. The encoded protein catalyzes the reduction of glutamate to delta1-pyrroline-5-carboxylate, a critical step in the de novo biosynthesis of proline, ornithine and arginine. Mutations in this gene lead to hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia and hypoprolinemia and may be associated with neurodegeneration, cataracts and connective tissue diseases. Alternatively spliced transcript variants, encoding different isoforms, have been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.751
• PP5: Variant 10-95633012-C-T is Pathogenic according to our data. Variant chr10-95633012-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-95633012-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH18A1	NM_002860.4	c.755G>A	p.Arg252Gln	missense_variant	7/18	ENST00000371224.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH18A1	ENST00000371224.7	c.755G>A	p.Arg252Gln	missense_variant	7/18	1	NM_002860.4	P3
ALDH18A1	ENST00000371221.3	c.749G>A	p.Arg250Gln	missense_variant	7/18	1		A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 23, 2021	Published functional studies suggest a damaging effect; specifically, in vitro functional expression assays show the mutant protein localizes normally to the mitochondria but low enzymatic activity (Panza et al., 2016); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33573605, 26026163, 26297558, 31692161) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Hereditary spastic paraplegia 9A Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 21, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Feb 08, 2018	- -

ALDH18A1 deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 17, 2020

The ALDH18A1 c.755G>A (p.Arg252Gln) variant is a missense variant and has been reported in a heterozygous state in at least three unrelated affected individuals presenting with moderate to severe pyramidal signs, pes cavus, cataracts, gastro-oesophageal reflux, chronic cellulitis, and cortical atrophy (Panza et al. 2006; Coutelier et al. 2015). Segregation of the p.Arg252Gln variant with disease was observed in one family in seven affected members over three generations and was absent in all unaffected members (Panza et al. 2016). Functional studies with recombinant p.Arg252Gln variant protein demonstrated that the enzyme activity was reduced compared to wild type (Panza et al. 2016). In addition, the p.Arg252 residue lies in the glutamate-5-kinase domain and is predicted by modelling to lie within the active site (Panza et al. 2006; Coutelier et al. 2015). The p.Arg252Gln variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence and application of ACMG criteria, the p.Arg252Gln variant is classified as pathogenic for ALDH18A1 deficiency. -

de Barsy syndrome;C1832669:Autosomal dominant spastic paraplegia type 9;C4225268:Cutis laxa, autosomal dominant 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 11, 2024

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 252 of the ALDH18A1 protein (p.Arg252Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant hereditary spastic paraplegia (PMID: 26026163, 26297558). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217117). 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 ALDH18A1 protein function. Experimental studies have shown that this missense change affects ALDH18A1 function (PMID: 26297558). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	T;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.038	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	0.99	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.4	N;N
REVEL	Uncertain	0.43
Sift	Benign	0.23	T;T
Sift4G	Benign	0.26	T;T
Polyphen		1.0	D;D
Vest4		0.64
MutPred		0.66		Gain of catalytic residue at R252 (P = 0.0428);.;
MVP		0.74
MPC		2.0
ClinPred		0.96	D
GERP RS		6.0
Varity_R		0.46
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs864321670; hg19: chr10-97392769;