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NM_003477.3(PDHX):c.44G>A (p.Arg15His) AND not provided

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Nov 2, 2022
Review status:
criteria provided, conflicting classifications
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000198591.9

Allele description [Variation Report for NM_003477.3(PDHX):c.44G>A (p.Arg15His)]

NM_003477.3(PDHX):c.44G>A (p.Arg15His)

Genes:
LOC130005549:ATAC-STARR-seq lymphoblastoid active region 4608 [Gene]
PDHX:pyruvate dehydrogenase complex component X [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
11p13
Genomic location:
Preferred name:
NM_003477.3(PDHX):c.44G>A (p.Arg15His)
Other names:
p.R15H:CGT>CAT
HGVS:
  • NC_000011.10:g.34916699G>A
  • NG_013368.1:g.5570G>A
  • NM_001135024.2:c.-21+213G>A
  • NM_001166158.2:c.44G>A
  • NM_003477.3:c.44G>AMANE SELECT
  • NP_001159630.1:p.Arg15His
  • NP_003468.2:p.Arg15His
  • NC_000011.9:g.34938246G>A
  • NM_003477.2:c.44G>A
Protein change:
R15H; ARG15HIS
Links:
OMIM: 608769.0010; dbSNP: rs387906998
NCBI 1000 Genomes Browser:
rs387906998
Molecular consequence:
  • NM_001135024.2:c.-21+213G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001166158.2:c.44G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003477.3:c.44G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000252060GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)
Likely benign
(Mar 3, 2021)
germlineclinical testing

Citation Link,

SCV003250418Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Nov 2, 2022)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Deep sequencing reveals 50 novel genes for recessive cognitive disorders.

Najmabadi H, Hu H, Garshasbi M, Zemojtel T, Abedini SS, Chen W, Hosseini M, Behjati F, Haas S, Jamali P, Zecha A, Mohseni M, PĆ¼ttmann L, Vahid LN, Jensen C, Moheb LA, Bienek M, Larti F, Mueller I, Weissmann R, Darvish H, Wrogemann K, et al.

Nature. 2011 Sep 21;478(7367):57-63. doi: 10.1038/nature10423.

PubMed [citation]
PMID:
21937992

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From GeneDx, SCV000252060.14

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

Description

This variant is associated with the following publications: (PMID: 21937992)

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003250418.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 15 of the PDHX protein (p.Arg15His). This variant is present in population databases (rs387906998, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with pyruvate dehydrogenase deficiency (PMID: 21937992). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30752). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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

Last Updated: Nov 10, 2024