rs864321669

chr10-95633040-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_002860.4(ALDH18A1):c.727G>C(p.Val243Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/21 in silico tools predict a benign 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. V243D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALDH18A1 NM_002860.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.02

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-95633040-C-G is Pathogenic according to our data. Variant chr10-95633040-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217116.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH18A1	NM_002860.4	c.727G>C	p.Val243Leu	missense_variant	7/18	ENST00000371224.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH18A1	ENST00000371224.7	c.727G>C	p.Val243Leu	missense_variant	7/18	1	NM_002860.4	P3
ALDH18A1	ENST00000371221.3	c.721G>C	p.Val241Leu	missense_variant	7/18	1		A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 9A Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 21, 2015

- -

P5CS deficiency Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Aug 15, 2023

The ALDH18A1 c.727G>C (p.Val243Leu) missense variant has been reported in a heterozygous state in one family with a phenotype which included bilateral cataracts, gastroesophageal reflux with persistent vomiting, and spastic paraparesis with amyotrophy (PMID:26297558). The variant segregated with disease in eleven affected family members over three generations and was absent in all unaffected members tested. Functional studies with recombinant p.Val243Leu variant protein demonstrated that the enzyme activity was reduced compared to wild type (PMID:26297558). In addition, the p.Val243 residue lies in the glutamate-5-kinase domain and is predicted by modelling to reside within the catalytic region (PMID:26297558). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Based on the available evidence, the c.727G>C (p.Val243Leu) is classified as likely pathogenic for P5CS deficiency. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.0086	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.28	T;.
Eigen	Benign	-0.072
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	-0.090	N;.
MutationTaster	Benign	0.76	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.84	N;N
REVEL	Benign	0.17
Sift	Benign	0.29	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.0010	B;B
Vest4		0.81
MutPred		0.48		Gain of solvent accessibility (P = 0.0156);.;
MVP		0.40
MPC		0.91
ClinPred		0.71	D
GERP RS		5.9
Varity_R		0.077
gMVP		0.89

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: rs864321669; hg19: chr10-97392797;