NM_152783.5(D2HGDH):c.1039G>A (p.Ala347Thr) AND D-2-hydroxyglutaric aciduria 1

Clinical significance:Uncertain significance (Last evaluated: Feb 24, 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:
RCV001035164.3

Allele description [Variation Report for NM_152783.5(D2HGDH):c.1039G>A (p.Ala347Thr)]

NM_152783.5(D2HGDH):c.1039G>A (p.Ala347Thr)

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.1039G>A (p.Ala347Thr)
HGVS:
  • NC_000002.12:g.241751287G>A
  • NG_012012.1:g.21673G>A
  • NM_001287249.2:c.637G>A
  • NM_001352824.2:c.478G>A
  • NM_152783.5:c.1039G>AMANE SELECT
  • NP_001274178.1:p.Ala213Thr
  • NP_001339753.1:p.Ala160Thr
  • NP_689996.4:p.Ala347Thr
  • NC_000002.11:g.242690702G>A
  • NM_152783.3:c.1039G>A
  • NM_152783.4:c.1039G>A
Protein change:
A160T
Molecular consequence:
  • NM_001287249.2:c.637G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001352824.2:c.478G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_152783.5:c.1039G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001198479Invitaecriteria provided, single submitter
Uncertain significance
(Feb 24, 2020)
germlineclinical testing

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

SCV001526226Baylor Geneticscriteria provided, single submitter
Uncertain significance
(Nov 16, 2018)
paternalclinical testing

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

Summary from all submissions

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

Citations

PubMed

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

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

Details of each submission

From Invitae, SCV001198479.2

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

Description

This sequence change replaces alanine with threonine at codon 347 of the D2HGDH protein (p.Ala347Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs142624021, ExAC 0.06%). This variant has not been reported in the literature in individuals with D2HGDH-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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

From Baylor Genetics, SCV001526226.1

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

Description

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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

Last Updated: Oct 7, 2021

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