NM_003748.4(ALDH4A1):c.1571G>A (p.Arg524Gln) AND Hyperprolinemia type 2

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jul 13, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001004742.11

Allele description

NM_003748.4(ALDH4A1):c.1571G>A (p.Arg524Gln)

Gene:

ALDH4A1:aldehyde dehydrogenase 4 family member A1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p36.13

Genomic location:

Preferred name:

NM_003748.4(ALDH4A1):c.1571G>A (p.Arg524Gln)

HGVS:

NC_000001.11:g.18874471C>T
NG_012283.1:g.33329G>A
NM_001161504.2:c.1391G>A
NM_001319218.2:c.1418G>A
NM_003748.4:c.1571G>AMANE SELECT
NM_170726.3:c.1571G>A
NP_001154976.1:p.Arg464Gln
NP_001306147.1:p.Arg473Gln
NP_003739.2:p.Arg524Gln
NP_733844.1:p.Arg524Gln
NC_000001.10:g.19200965C>T
NC_000001.10:g.19200965C>T
NM_003748.3:c.1571G>A

Protein change:

R464Q

Links:

Molecular consequence:

NM_001161504.2:c.1391G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001319218.2:c.1418G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003748.4:c.1571G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_170726.3:c.1571G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hyperprolinemia type 2 (HYRPRO2)
Synonyms:: 1-PYRROLINE-5-CARBOXYLATE DEHYDROGENASE DEFICIENCY; Delta-1-pyrroline-5-carboxylate dehydrogenase deficiency; Deficiency of pyrroline-5-carboxylate reductase
Identifiers:: MONDO: MONDO:0009401; MedGen: C2931835; Orphanet: 79101; OMIM: 239510

Recent activity

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Glycine max soyasaponin III rhamnosyltransferase (SGT3), mRNA
Glycine max soyasaponin III rhamnosyltransferase (SGT3), mRNA
gi|1334575485|ref|NM_001253928.2|

Nucleotide
calcium/calmodulin-dependent protein kinase type 1G isoform X1 [Homo sapiens]
calcium/calmodulin-dependent protein kinase type 1G isoform X1 [Homo sapiens]
gi|2462511669|ref|XP_054193773.1|

Protein
Glycine max SDL12A (LOC547855), mRNA
Glycine max SDL12A (LOC547855), mRNA
gi|1199701026|ref|NM_001248246.2|

Nucleotide
Nemertesia norvegica mitochondrial partial 16S rRNA gene, isolated from Atlantis...
Nemertesia norvegica mitochondrial partial 16S rRNA gene, isolated from Atlantis Seamount, Portugal
gi|161338567|emb|AM888330.1|

Nucleotide
Vigna vexillata cultivar TVnu 1623 gibberellin 2-beta-dioxygenase 1-1 protein ge...
Vigna vexillata cultivar TVnu 1623 gibberellin 2-beta-dioxygenase 1-1 protein gene, complete cds
gi|2727548497|gb|OQ927384.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001255206	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Jan 12, 2018)	germline	clinical testing	Citation Link,
SCV003028041	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 13, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001255206

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Jan 12, 2018)

germline

clinical testing

Citation Link,

SCV003028041

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 13, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Génétique des Maladies du Développement, Hospices Civils de Lyon, SCV001164219.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV001255206.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV003028041.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 813795). This variant has not been reported in the literature in individuals affected with ALDH4A1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 524 of the ALDH4A1 protein (p.Arg524Gln).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001164219	Génétique des Maladies du Développement, Hospices Civils de Lyon	flagged submission Reason: Older claim that does not account for recent evidence Notes: None (ACMG Guidelines, 2015)	Likely pathogenic (Aug 21, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001164219

Génétique des Maladies du Développement, Hospices Civils de Lyon

flagged submission

Reason: Older claim that does not account for recent evidence

Notes: None

(ACMG Guidelines, 2015)

Likely pathogenic
(Aug 21, 2018)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Last Updated: Jun 23, 2024

ClinVar

Relating variation to medicine