rs863225044

chr10-95637328-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_002860.4(ALDH18A1):c.412C>T(p.Arg138Trp) variant causes a missense change involving the alteration of a non-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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R138Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALDH18A1 NM_002860.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.888

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 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_002860.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-95637327-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 217260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88
• PP5: Variant 10-95637328-G-A is Pathogenic according to our data. Variant chr10-95637328-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 217259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-95637328-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH18A1	NM_002860.4	c.412C>T	p.Arg138Trp	missense_variant	4/18	ENST00000371224.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH18A1	ENST00000371224.7	c.412C>T	p.Arg138Trp	missense_variant	4/18	1	NM_002860.4	P3
ALDH18A1	ENST00000371221.3	c.412C>T	p.Arg138Trp	missense_variant	4/18	1		A1
ALDH18A1	ENST00000483788.1	n.604C>T		non_coding_transcript_exon_variant	4/5	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cutis laxa, autosomal dominant 3 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	The variantwas confirmed as de novo by parental testing. The same variant was also reported as de novo in one or more affected individuals with a consistent phenotype from multiple, unrelated families (PMID: 26320891) (PS2_VS). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000217259, PMID:26320891, PS1_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000217261, PMID:26320891,26320891, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.821, 3CNET: 0.985, PP3_P). A missense variant is a common mechanism associated with Cutis laxa (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2019	This variant was identified as de novo (maternity and paternity confirmed). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 03, 2015	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 10, 2021

Published functional studies demonstrate a damaging effect with significantly altered distribution of the ALDH18A1 protein within the mitochondrial network and reduced enzyme activity (Fischer-Zirnsak et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26320891) -

Cutis laxa, autosomal dominant 3;C5234852:ALDH18A1-related de Barsy syndrome;C5568978:Hereditary spastic paraplegia 9A;C5568980:Autosomal recessive complex spastic paraplegia type 9B Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Lab, CHRU Brest

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.5	D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.96
MutPred		0.59		Loss of disorder (P = 0.0067);Loss of disorder (P = 0.0067);
MVP		0.88
MPC		1.9
ClinPred		0.99	D
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.65
gMVP		0.91

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: rs863225044; hg19: chr10-97397085; COSMIC: COSV64662240;