NM_003748.4(ALDH4A1):c.866+1G>A AND Deficiency of pyrroline-5-carboxylate reductase

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(2);Uncertain significance(1) (Last evaluated: Dec 19, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000505674.5

Allele description [Variation Report for NM_003748.4(ALDH4A1):c.866+1G>A]

NM_003748.4(ALDH4A1):c.866+1G>A

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.866+1G>A
HGVS:
  • NC_000001.11:g.18881699C>T
  • NG_012283.1:g.26101G>A
  • NM_001161504.2:c.686+1G>A
  • NM_001319218.2:c.866+1G>A
  • NM_003748.4:c.866+1G>AMANE SELECT
  • NM_170726.3:c.866+1G>A
  • NC_000001.10:g.19208193C>T
  • NM_003748.3:c.866+1G>A
Links:
dbSNP: rs78532707
NCBI 1000 Genomes Browser:
rs78532707
Molecular consequence:
  • NM_001161504.2:c.686+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001319218.2:c.866+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_003748.4:c.866+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_170726.3:c.866+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000599974Donald Williams Parsons Laboratory,Baylor College of Medicine - CSER-BASIC3

See additional submitters

no assertion criteria providedPathogenic
(Nov 17, 2014)
maternalresearch

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

SCV000826155Invitaecriteria provided, single submitter
Likely pathogenic
(Sep 19, 2018)
germlineclinical testing

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

SCV000914371Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Uncertain significance
(Nov 19, 2018)
germlineclinical testing

Citation Link,

SCV001521274Baylor Geneticscriteria provided, single submitter
Likely pathogenic
(Dec 19, 2019)
unknownclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
Causasians,Hispanic Americansmaternalunknown11not providednot providednot providedresearch

Citations

PubMed

Diagnostic Yield of Clinical Tumor and Germline Whole-Exome Sequencing for Children With Solid Tumors.

Parsons DW, Roy A, Yang Y, Wang T, Scollon S, Bergstrom K, Kerstein RA, Gutierrez S, Petersen AK, Bavle A, Lin FY, López-Terrada DH, Monzon FA, Hicks MJ, Eldin KW, Quintanilla NM, Adesina AM, Mohila CA, Whitehead W, Jea A, Vasudevan SA, Nuchtern JG, et al.

JAMA Oncol. 2016 May 1;2(5):616-624. doi: 10.1001/jamaoncol.2015.5699.

PubMed [citation]
PMID:
26822237
PMCID:
PMC5471125

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):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818
See all PubMed Citations (3)

Details of each submission

From Donald Williams Parsons Laboratory,Baylor College of Medicine - CSER-BASIC3, SCV000599974.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Causasians,Hispanic Americans1not providednot providedresearch
(GTR000508680.4)
PubMed (1)

Description

This splice site variant is categorized as deleterious according to ACMG guidelines (PMID:18414213). It would be pathogenic in a recessive state; heterozygotes would be carriers for the condition. It was found once in our study heterozygous, maternally inherited in a 12-year-old female with pilocytic astrocytoma and intellectual disability.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1maternalunknownnot providednot providednot provided
(GTR000508680.4)
1not provided1not provided

From Invitae, SCV000826155.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This sequence change affects a donor splice site in intron 8 of the ALDH4A1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs78532707, ExAC 0.009%). This variant has not been reported in the literature in individuals with ALDH4A1-related disease. ClinVar contains an entry for this variant (Variation ID: 438800). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ALDH4A1 are known to be pathogenic (PMID: 9700195, 4369405, 956388). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Illumina Clinical Services Laboratory,Illumina, SCV000914371.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The ALDH4A1 c.866+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. It was observed by ICSL 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 for this variant, it 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 and cDNA change. No publications were found based on this search. Due to the potential impact of splice donor variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for hyperprolinemia.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Baylor Genetics, SCV001521274.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

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