NM_006859.4:c.64dupT

Variant names:

• chr4-39460803-A-AT
• rs960319940
• NM_006859.4:c.64dupT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_006859.4(LIAS):​c.64dupT​(p.Cys22LeufsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LIAS NM_006859.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.567
• Publications: 0 publications found

Genes affected

LIAS (HGNC:16429): (lipoic acid synthetase) The protein encoded by this gene belongs to the biotin and lipoic acid synthetases family. Localized in the mitochondrion, this iron-sulfur enzyme catalyzes the final step in the de novo pathway for the biosynthesis of lipoic acid, a potent antioxidant. The deficient expression of this enzyme has been linked to conditions such as diabetes, atherosclerosis and neonatal-onset epilepsy. Alternative splicing occurs at this locus, and several transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Aug 2020]

LIAS Gene-Disease associations (from GenCC):

• lipoic acid synthetase deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ENSG00000298395 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 29 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-39460803-A-AT is Pathogenic according to our data. Variant chr4-39460803-A-AT is described in CliVar as Pathogenic. Clinvar id is 540088.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-39460803-A-AT is described in CliVar as Pathogenic. Clinvar id is 540088.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-39460803-A-AT is described in CliVar as Pathogenic. Clinvar id is 540088.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-39460803-A-AT is described in CliVar as Pathogenic. Clinvar id is 540088.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-39460803-A-AT is described in CliVar as Pathogenic. Clinvar id is 540088.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-39460803-A-AT is described in CliVar as Pathogenic. Clinvar id is 540088.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-39460803-A-AT is described in CliVar as Pathogenic. Clinvar id is 540088.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-39460803-A-AT is described in CliVar as Pathogenic. Clinvar id is 540088.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-39460803-A-AT is described in CliVar as Pathogenic. Clinvar id is 540088.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-39460803-A-AT is described in CliVar as Pathogenic. Clinvar id is 540088.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-39460803-A-AT is described in CliVar as Pathogenic. Clinvar id is 540088.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-39460803-A-AT is described in CliVar as Pathogenic. Clinvar id is 540088.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-39460803-A-AT is described in CliVar as Pathogenic. Clinvar id is 540088.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-39460803-A-AT is described in CliVar as Pathogenic. Clinvar id is 540088.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-39460803-A-AT is described in CliVar as Pathogenic. Clinvar id is 540088.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-39460803-A-AT is described in CliVar as Pathogenic. Clinvar id is 540088.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-39460803-A-AT is described in CliVar as Pathogenic. Clinvar id is 540088.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-39460803-A-AT is described in CliVar as Pathogenic. Clinvar id is 540088.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-39460803-A-AT is described in CliVar as Pathogenic. Clinvar id is 540088.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIAS	NM_006859.4	c.64dupT	p.Cys22LeufsTer13	frameshift_variant	Exon 2 of 11	ENST00000640888.2	NP_006850.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIAS	ENST00000640888.2	c.64dupT	p.Cys22LeufsTer13	frameshift_variant	Exon 2 of 11	1	NM_006859.4	ENSP00000492260.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lipoic acid synthetase deficiency Pathogenic:1

Aug 03, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Cys22Leufs*13) in the LIAS gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with LIAS-related disease. Loss-of-function variants in LIAS are known to be pathogenic (PMID: 26108146). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.57
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs960319940; hg19: chr4-39462423;