NM_152783.5(D2HGDH):c.1453G>A (p.Val485Ile) AND D-2-hydroxyglutaric aciduria 1

Clinical significance:Uncertain significance (Last evaluated: Feb 22, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_152783.5(D2HGDH):c.1453G>A (p.Val485Ile)]

NM_152783.5(D2HGDH):c.1453G>A (p.Val485Ile)

D2HGDH:D-2-hydroxyglutarate dehydrogenase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_152783.5(D2HGDH):c.1453G>A (p.Val485Ile)
  • NC_000002.12:g.241767856G>A
  • NG_012012.1:g.38242G>A
  • NM_001287249.2:c.1051G>A
  • NM_001352824.2:c.892G>A
  • NM_152783.5:c.1453G>AMANE SELECT
  • NP_001274178.1:p.Val351Ile
  • NP_001339753.1:p.Val298Ile
  • NP_689996.4:p.Val485Ile
  • NC_000002.11:g.242707271G>A
  • NM_152783.3:c.1453G>A
  • NM_152783.4:c.1453G>A
  • NR_109778.2:n.1324G>A
Protein change:
dbSNP: rs375162898
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_001287249.2:c.1051G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001352824.2:c.892G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_152783.5:c.1453G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_109778.2:n.1324G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]


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

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000429416Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Uncertain significance
(Jan 13, 2018)
germlineclinical testing

Citation Link,

SCV001393347Invitaecriteria provided, single submitter
Uncertain significance
(Feb 22, 2020)
germlineclinical 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



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]

Details of each submission

From Illumina Clinical Services Laboratory,Illumina, SCV000429416.3

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


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.

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

From Invitae, SCV001393347.2

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


This sequence change replaces valine with isoleucine at codon 485 of the D2HGDH protein (p.Val485Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs375162898, ExAC 0.1%). This variant has not been reported in the literature in individuals with D2HGDH-related conditions. ClinVar contains an entry for this variant (Variation ID: 335320). 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.

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

Last Updated: Oct 7, 2021

Support Center