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NM_000284.4(PDHA1):c.746T>G (p.Ile249Ser) AND not provided

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
May 17, 2013
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV000486536.1

Allele description [Variation Report for NM_000284.4(PDHA1):c.746T>G (p.Ile249Ser)]

NM_000284.4(PDHA1):c.746T>G (p.Ile249Ser)

Gene:
PDHA1:pyruvate dehydrogenase E1 subunit alpha 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Xp22.12
Genomic location:
Preferred name:
NM_000284.4(PDHA1):c.746T>G (p.Ile249Ser)
HGVS:
  • NC_000023.11:g.19355491T>G
  • NG_016781.1:g.16599T>G
  • NM_000284.4:c.746T>GMANE SELECT
  • NM_001173454.2:c.860T>G
  • NM_001173455.2:c.767T>G
  • NM_001173456.2:c.653T>G
  • NP_000275.1:p.Ile249Ser
  • NP_001166925.1:p.Ile287Ser
  • NP_001166926.1:p.Ile256Ser
  • NP_001166927.1:p.Ile218Ser
  • NC_000023.10:g.19373609T>G
  • NM_000284.3:c.746T>G
Protein change:
I218S
Links:
dbSNP: rs1064793225
NCBI 1000 Genomes Browser:
rs1064793225
Molecular consequence:
  • NM_000284.4:c.746T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001173454.2:c.860T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001173455.2:c.767T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001173456.2:c.653T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: CN517202

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000565366GeneDx
criteria provided, single submitter

(GeneDx Variant Classification (06012015))		Likely pathogenic
(May 17, 2013) 		germlineclinical testing

Citation Link

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Summary from all submissions

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

Details of each submission

From GeneDx, SCV000565366.2

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

Description

A novel I249S missense change that is likely pathogenic was identified in the PDHA1 gene. It has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The amino acid change is non-conservative as a non-polar Isoleucine residue is replaced by a polar Serine residue. This change occurs at a highly conserved position in the PDHA1 protein, and missense variants at nearby positions (Y243C, Y243S, R245G, P250L, P250T, R253G) have been reported in association with pyruvate dehydrogenase deficiency according to the Human Gene Mutation Database. Furthermore, multiple in-silico analysis programs predict that I249S is damaging to the PDHA1 protein. Therefore, I249S is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.

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

Last Updated: Apr 23, 2022