NM_006859.4(LIAS):c.218G>C (p.Arg73Thr) AND Pyruvate dehydrogenase lipoic acid synthetase deficiency

Clinical significance:Uncertain significance (Last evaluated: Jun 2, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000526052.1

Allele description [Variation Report for NM_006859.4(LIAS):c.218G>C (p.Arg73Thr)]

NM_006859.4(LIAS):c.218G>C (p.Arg73Thr)

Gene:
LIAS:lipoic acid synthetase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
4p14
Genomic location:
Preferred name:
NM_006859.4(LIAS):c.218G>C (p.Arg73Thr)
HGVS:
  • NC_000004.12:g.39460962G>C
  • NG_032111.1:g.6918G>C
  • NG_052985.1:g.2987C>G
  • NM_001278590.2:c.218G>C
  • NM_001278591.2:c.218G>C
  • NM_001278592.2:c.218G>C
  • NM_001363700.2:c.218G>C
  • NM_006859.4:c.218G>CMANE SELECT
  • NM_194451.3:c.218G>C
  • NP_001265519.1:p.Arg73Thr
  • NP_001265520.1:p.Arg73Thr
  • NP_001265521.1:p.Arg73Thr
  • NP_001350629.1:p.Arg73Thr
  • NP_006850.2:p.Arg73Thr
  • NP_919433.1:p.Arg73Thr
  • LRG_1142:g.2987C>G
  • NC_000004.11:g.39462582G>C
  • NM_006859.3:c.218G>C
Protein change:
R73T
Links:
dbSNP: rs1172950083
NCBI 1000 Genomes Browser:
rs1172950083
Molecular consequence:
  • NM_001278590.2:c.218G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001278591.2:c.218G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001278592.2:c.218G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001363700.2:c.218G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_006859.4:c.218G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_194451.3:c.218G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Pyruvate dehydrogenase lipoic acid synthetase deficiency (HGCLAS)
Synonyms:
HYPERGLYCINEMIA, LACTIC ACIDOSIS, AND SEIZURES
Identifiers:
MONDO: MONDO:0013762; MedGen: C3280887; Orphanet: 401859; OMIM: 614462

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000652148Invitaecriteria provided, single submitter
Uncertain significance
(Jun 2, 2017)
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

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

Details of each submission

From Invitae, SCV000652148.1

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

Description

This sequence change replaces arginine with threonine at codon 73 of the LIAS protein (p.Arg73Thr). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and threonine. This variant also falls at the last nucleotide of exon 2 of the LIAS coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a LIAS-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a novel missense change with uncertain impact on RNA splicing and protein function. It has been classified as a Variant of Uncertain Significance.

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

Last Updated: Nov 27, 2021

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