NM_006859.4(LIAS):c.120G>T (p.Gln40His) AND Pyruvate dehydrogenase lipoic acid synthetase deficiency

Clinical significance:Uncertain significance (Last evaluated: May 20, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000542397.4

Allele description [Variation Report for NM_006859.4(LIAS):c.120G>T (p.Gln40His)]

NM_006859.4(LIAS):c.120G>T (p.Gln40His)

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.120G>T (p.Gln40His)
HGVS:
  • NC_000004.12:g.39460864G>T
  • NG_032111.1:g.6820G>T
  • NG_052985.1:g.3085C>A
  • NM_001278590.2:c.120G>T
  • NM_001278591.2:c.120G>T
  • NM_001278592.2:c.120G>T
  • NM_001363700.2:c.120G>T
  • NM_006859.4:c.120G>TMANE SELECT
  • NM_194451.3:c.120G>T
  • NP_001265519.1:p.Gln40His
  • NP_001265520.1:p.Gln40His
  • NP_001265521.1:p.Gln40His
  • NP_001350629.1:p.Gln40His
  • NP_006850.2:p.Gln40His
  • NP_919433.1:p.Gln40His
  • LRG_1142:g.3085C>A
  • NC_000004.11:g.39462484G>T
  • NM_006859.3:c.120G>T
Protein change:
Q40H
Links:
dbSNP: rs1041843537
NCBI 1000 Genomes Browser:
rs1041843537
Molecular consequence:
  • NM_001278590.2:c.120G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001278591.2:c.120G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001278592.2:c.120G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001363700.2:c.120G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_006859.4:c.120G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_194451.3:c.120G>T - 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
SCV000652146Invitaecriteria provided, single submitter
Uncertain significance
(May 20, 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

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, SCV000652146.4

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

Description

This sequence change replaces glutamine with histidine at codon 40 of the LIAS protein (p.Gln40His). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and histidine. 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 output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, 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: Oct 30, 2021

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