NM_152783.5(D2HGDH):c.659A>G (p.His220Arg) AND D-2-hydroxyglutaric aciduria 1

Clinical significance:Uncertain significance (Last evaluated: Feb 17, 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:
RCV000820346.2

Allele description [Variation Report for NM_152783.5(D2HGDH):c.659A>G (p.His220Arg)]

NM_152783.5(D2HGDH):c.659A>G (p.His220Arg)

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.659A>G (p.His220Arg)
HGVS:
  • NC_000002.12:g.241743790A>G
  • NG_012012.1:g.14176A>G
  • NM_001287249.2:c.257A>G
  • NM_001352824.2:c.98A>G
  • NM_152783.5:c.659A>GMANE SELECT
  • NP_001274178.1:p.His86Arg
  • NP_001339753.1:p.His33Arg
  • NP_689996.4:p.His220Arg
  • NC_000002.11:g.242683205A>G
  • NM_152783.3:c.659A>G
  • NM_152783.4:c.659A>G
  • NR_109778.2:n.817A>G
Protein change:
H220R
Links:
dbSNP: rs112424377
NCBI 1000 Genomes Browser:
rs112424377
Molecular consequence:
  • NM_001287249.2:c.257A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001352824.2:c.98A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_152783.5:c.659A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NR_109778.2:n.817A>G - 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
SCV000961055Invitaecriteria provided, single submitter
Uncertain significance
(Nov 14, 2018)
germlineclinical testing

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

SCV001519861Baylor Geneticscriteria provided, single submitter
Uncertain significance
(Feb 17, 2020)
unknownclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownyesnot 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, SCV000961055.1

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

Description

This sequence change replaces histidine with arginine at codon 220 of the D2HGDH protein (p.His220Arg). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs112424377, ExAC 0.1%). 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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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, SCV001519861.1

#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
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 7, 2021

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