Gene Validity Curation

ALDH4A1 - hyperprolinemia type 2

Gene: ALDH4A1 (HGNC:406)
Classification - 09/13/2019
Disease: hyperprolinemia type 2 (MONDO_0009401)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: NO Contradictory Evidence: NO
Expert Panel: Aminoacidopathy EP
Evidence Summary: The relationship between ALDH4A1 and hyperprolinemia type II, an autosomal recessive disorder of proline metabolism, was evaluated using the ClinGen Clinical Validity Framework as of September 11th, 2019. ALDH4A1 encodes delta1-pyrroline-5-carboxylic acid dehydrogenase (P5CDH), a mitochondrial matrix protein that catalyzes the conversion of L-glutamate-γ-semialdehyde, the hydrolysis product of delta1-pyrroline-5-carboxylate (P5C), to L-glutamate. Individuals with hyperprolinemia type II have elevated P5C levels, elevated proline (due to the conversion of P5C to proline), and positive o-aminobenzaldehyde reaction in urine (due to presence of delta-pyrroline products). Some patients with hyperprolinemia have seizures, but most are clinically unaffected. Biallelic variants in ALDH4A1 were first reported in 1998 by Geraghty et al (PMID 9700195); this is currently the only available publication reporting variants in ALDH4A1 in individuals with hyperprolinemia type II. Data from 3 patients who are homozygous or compound heterozygous for ALDH4A1 variants were curated, including 3 unique variants (one missense and two frameshift variants). One of these variants, c.1560dup, was found to be homozygous in 7 individuals (a father and 6 affected children), and heterozygous in an unaffected sibling, in a branch of a large Irish traveler family (Flynn et al, 1989, PMID 2624476). Another individual with hyperprolinemia type II was reported to be homozygous for a missense variant, p.Pro16Leu, in ALDH4A1, but this variant is probably benign based on the allele frequency and results of functional studies (PMID 9700195). This gene-disease relationship is supported by the biochemical function of P5CDH which is consistent with the biochemical differences observed in individuals with hyperprolinemia type II (Strecker, 1960, PMID 13835167; Valle et al, 1974, 4369405). P5C, which accumulates in individuals with hyperprolinemia type II, has been shown to react with pyridoxal phosphate, providing an explanation for Vitamin B6 deficiency in a patient with this condition, and a possible cause for seizures in affected individuals. This led to the suggestion that individuals with hyperprolinemia type II may benefit from treatment with Vitamin B6 (Farrant et al, 2001, PMID 11134058). However, other individuals with hyperprolinemia type II have low-normal Vitamin B6 levels, and treatment with Vitamin B6 had no impact on their symptoms (van den Ven et al, 2014, PMID 24173411). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This clinical validity classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel.
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 3
6
6
Geraghty MT et al. 1998 Sep (PMID:9700195);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 1
0
Geraghty MT et al. 1998 Sep (PMID:9700195);
Segregation Evidence   Summed LOD Family Count 1 1  
Candidate gene sequencing 3.14 1
Geraghty MT et al. 1998 Sep (PMID:9700195);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 3.14    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 7
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 2
1
1
Valle DL et al. 1974 Sep 20 (PMID:4369405); STRECKER HJ et al. 1960 Jul (PMID:13835167);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 1

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 7 1 8 NO
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Moderate
09/13/2019
EXPERT CURATION (DATE)
Moderate
09/13/2019
EVIDENCE SUMMARY
The relationship between ALDH4A1 and hyperprolinemia type II, an autosomal recessive disorder of proline metabolism, was evaluated using the ClinGen Clinical Validity Framework as of September 11th, 2019. ALDH4A1 encodes delta1-pyrroline-5-carboxylic acid dehydrogenase (P5CDH), a mitochondrial matrix protein that catalyzes the conversion of L-glutamate-γ-semialdehyde, the hydrolysis product of delta1-pyrroline-5-carboxylate (P5C), to L-glutamate. Individuals with hyperprolinemia type II have elevated P5C levels, elevated proline (due to the conversion of P5C to proline), and positive o-aminobenzaldehyde reaction in urine (due to presence of delta-pyrroline products). Some patients with hyperprolinemia have seizures, but most are clinically unaffected. Biallelic variants in ALDH4A1 were first reported in 1998 by Geraghty et al (PMID 9700195); this is currently the only available publication reporting variants in ALDH4A1 in individuals with hyperprolinemia type II. Data from 3 patients who are homozygous or compound heterozygous for ALDH4A1 variants were curated, including 3 unique variants (one missense and two frameshift variants). One of these variants, c.1560dup, was found to be homozygous in 7 individuals (a father and 6 affected children), and heterozygous in an unaffected sibling, in a branch of a large Irish traveler family (Flynn et al, 1989, PMID 2624476). Another individual with hyperprolinemia type II was reported to be homozygous for a missense variant, p.Pro16Leu, in ALDH4A1, but this variant is probably benign based on the allele frequency and results of functional studies (PMID 9700195). This gene-disease relationship is supported by the biochemical function of P5CDH which is consistent with the biochemical differences observed in individuals with hyperprolinemia type II (Strecker, 1960, PMID 13835167; Valle et al, 1974, 4369405). P5C, which accumulates in individuals with hyperprolinemia type II, has been shown to react with pyridoxal phosphate, providing an explanation for Vitamin B6 deficiency in a patient with this condition, and a possible cause for seizures in affected individuals. This led to the suggestion that individuals with hyperprolinemia type II may benefit from treatment with Vitamin B6 (Farrant et al, 2001, PMID 11134058). However, other individuals with hyperprolinemia type II have low-normal Vitamin B6 levels, and treatment with Vitamin B6 had no impact on their symptoms (van den Ven et al, 2014, PMID 24173411). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This clinical validity classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel.