NM_152783.5(D2HGDH):c.697G>A (p.Gly233Ser) AND D-2-hydroxyglutaric aciduria 1

Clinical significance:Uncertain significance (Last evaluated: Aug 5, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV001142182.2

Allele description [Variation Report for NM_152783.5(D2HGDH):c.697G>A (p.Gly233Ser)]

NM_152783.5(D2HGDH):c.697G>A (p.Gly233Ser)

Gene:
D2HGDH:D-2-hydroxyglutarate dehydrogenase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q37.3
Genomic location:
Preferred name:
NM_152783.5(D2HGDH):c.697G>A (p.Gly233Ser)
HGVS:
  • NC_000002.12:g.241744721G>A
  • NG_012012.1:g.15107G>A
  • NM_001287249.2:c.295G>A
  • NM_001352824.2:c.136G>A
  • NM_152783.5:c.697G>AMANE SELECT
  • NP_001274178.1:p.Gly99Ser
  • NP_001339753.1:p.Gly46Ser
  • NP_689996.4:p.Gly233Ser
  • NC_000002.11:g.242684136G>A
  • NM_152783.3:c.697G>A
  • NR_109778.2:n.855G>A
Protein change:
G233S
Links:
Molecular consequence:
  • NM_001287249.2:c.295G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001352824.2:c.136G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_152783.5:c.697G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_109778.2:n.855G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
D-2-hydroxyglutaric aciduria 1 (D2HGA1)
Identifiers:
MONDO: MONDO:0024554; MedGen: C3152055; Orphanet: 79315; OMIM: 600721

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001302594Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Uncertain significance
(Apr 28, 2017)
germlineclinical testing

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

Citation Link,

SCV001535083Invitaecriteria provided, single submitter
Uncertain significance
(Aug 5, 2020)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Evidence for genetic heterogeneity in D-2-hydroxyglutaric aciduria.

Kranendijk M, Struys EA, Gibson KM, Wickenhagen WV, Abdenur JE, Buechner J, Christensen E, de Kremer RD, Errami A, Gissen P, Gradowska W, Hobson E, Islam L, Korman SH, Kurczynski T, Maranda B, Meli C, Rizzo C, Sansaricq C, Trefz FK, Webster R, Jakobs C, et al.

Hum Mutat. 2010 Mar;31(3):279-83. doi: 10.1002/humu.21186.

PubMed [citation]
PMID:
20020533

D-2-hydroxyglutaric aciduria Type I: Functional analysis of D2HGDH missense variants.

Pop A, Struys EA, Jansen EEW, Fernandez MR, Kanhai WA, van Dooren SJM, Ozturk S, van Oostendorp J, Lennertz P, Kranendijk M, van der Knaap MS, Gibson KM, van Schaftingen E, Salomons GS.

Hum Mutat. 2019 Jul;40(7):975-982. doi: 10.1002/humu.23751. Epub 2019 Apr 13.

PubMed [citation]
PMID:
30908763
PMCID:
PMC6619364
See all PubMed Citations (3)

Details of each submission

From Illumina Clinical Services Laboratory,Illumina, SCV001302594.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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

From Invitae, SCV001535083.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces glycine with serine at codon 233 of the D2HGDH protein (p.Gly233Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs374535734, ExAC 0.003%). This variant has been observed in individual(s) with D-2-hydroxyglutaric aciduria (PMID: 20020533, Invitae). ClinVar contains an entry for this variant (Variation ID: 898353). This variant has been reported to affect D2HGDH protein function (PMID: 30908763). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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

Last Updated: Oct 7, 2021

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