NM_000284.4(PDHA1):c.1170_1171dup (p.Ter391PheextTer?) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 16, 2023
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:: RCV003405036.1

Allele description [Variation Report for NM_000284.4(PDHA1):c.1170_1171dup (p.Ter391PheextTer?)]

NM_000284.4(PDHA1):c.1170_1171dup (p.Ter391PheextTer?)

Gene:

PDHA1:pyruvate dehydrogenase E1 subunit alpha 1 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

Xp22.12

Genomic location:

Preferred name:

NM_000284.4(PDHA1):c.1170_1171dup (p.Ter391PheextTer?)

HGVS:

NC_000023.11:g.19359650_19359651dup
NG_016781.1:g.20758_20759dup
NG_021184.1:g.160611_160612dup
NM_000284.4:c.1170_1171dupMANE SELECT
NM_001173454.2:c.1284_1285dup
NM_001173455.2:c.1191_1192dup
NM_001173456.2:c.1077_1078dup
NP_000275.1:p.Ter391PheextTer?
NP_001166925.1:p.Ter429PheextTer?
NP_001166926.1:p.Ter398PheextTer?
NP_001166927.1:p.Ter360PheextTer?
NC_000023.10:g.19377768_19377769dup
NM_000284.4:c.1170_1171dupTTMANE SELECT

Molecular consequence:

NM_000284.4:c.1170_1171dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001173454.2:c.1284_1285dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001173455.2:c.1191_1192dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001173456.2:c.1077_1078dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_000284.4:c.1170_1171dup - stop lost - [Sequence Ontology: SO:0001578]
NM_001173454.2:c.1284_1285dup - stop lost - [Sequence Ontology: SO:0001578]
NM_001173455.2:c.1191_1192dup - stop lost - [Sequence Ontology: SO:0001578]
NM_001173456.2:c.1077_1078dup - stop lost - [Sequence Ontology: SO:0001578]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

Recent activity

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chromosomal replication initiator protein DnaA, partial [Burkholderia sp. RPE301...
chromosomal replication initiator protein DnaA, partial [Burkholderia sp. RPE301]
gi|347800066|dbj|BAK86411.1|

Protein
casein kinase I isoform gamma-3 isoform 11 [Homo sapiens]
casein kinase I isoform gamma-3 isoform 11 [Homo sapiens]
gi|1398130408|ref|NP_001351073.1|

Protein
nostrin isoform 4 [Homo sapiens]
nostrin isoform 4 [Homo sapiens]
gi|284172477|ref|NP_001165102.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004122917	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Oct 16, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004122917

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Oct 16, 2023)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Amino acid ratio combinations as biomarkers for discriminating patients with pyruvate dehydrogenase complex deficiency from other inborn errors of metabolism.

Verma A, Lehman AN, Gokcan H, Cropcho L, Black D, Dobrowolski SF, Vockley J, Bedoyan JK.

Mol Genet Genomic Med. 2024 Jan;12(1):e2283. doi: 10.1002/mgg3.2283. Epub 2023 Sep 8. Review.

PubMed [citation]

PMID:: 37688338
PMCID:: PMC10767461

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004122917.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Variant summary: PDHA1 c.1170_1171dupTT (p.X391Pheext*34) changes the termination codon and is predicted to lead to an extended protein with additional amino acids added to the normal C-terminus. The variant was absent in 183362 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1170_1171dupTT has been reported in the literature in the hemizygous state in an individual affected with Pyruvate Dehydrogenase Deficiency (Verma_2023). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 37688338). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 25, 2023

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