rs137891647

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_145199.3(LIPT1):c.875C>G(p.Ser292*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00069 in 1,613,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00072 ( 0 hom. )

Consequence

LIPT1
NM_145199.3 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 1.86

Variant links:

Genes affected

LIPT1 (HGNC:29569): (lipoyltransferase 1) The process of transferring lipoic acid to proteins is a two-step process. The first step is the activation of lipoic acid by lipoate-activating enzyme to form lipoyl-AMP. For the second step, the protein encoded by this gene transfers the lipoyl moiety to apoproteins. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 13. Read-through transcription also exists between this gene and the neighboring downstream mitochondrial ribosomal protein L30 (MRPL30) gene. [provided by RefSeq, Mar 2011]

LIPT1 links:

ENSG00000273155 (HGNC:):

ENSG00000273155 links:

MITD1 (HGNC:25207): (microtubule interacting and trafficking domain containing 1) Abscission, the separation of daughter cells at the end of cytokinesis, is effected by endosomal sorting complexes required for transport III (ESCRT-III). The protein encoded by this gene functions as a homodimer, with the N-termini binding to a subset of ESCRT-III subunits and the C-termini binding to membranes. The encoded protein regulates ESCRT-III activity and is required for proper cytokinesis. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2016]

MITD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.22 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-99162832-C-G is Pathogenic according to our data. Variant chr2-99162832-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 285871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIPT1	NM_145199.3 link	c.875C>G	p.Ser292*	stop_gained	Exon 2 of 2	ENST00000651691.1	NP_660200.1	Q9Y234

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LIPT1	ENST00000651691.1 link	c.875C>G	p.Ser292*	stop_gained	Exon 2 of 2		NM_145199.3	ENSP00000498546.1	Q9Y234
ENSG00000273155	ENST00000410042.1 link	c.-28+6406C>G		intron_variant	Intron 2 of 5	2		ENSP00000387111.1
ENSG00000241962	ENST00000424491.5 link	n.63+12313C>G		intron_variant	Intron 4 of 13	2		ENSP00000390891.1

Frequencies

GnomAD3 genomes

AF:

0.000447

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000363

AC:

AN:

250868

Hom.:

AF XY:

0.000346

AC XY:

AN XY:

135656

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000511

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000715

AC:

1045

AN:

1461412

Hom.:

Cov.:

AF XY:

0.000714

AC XY:

519

AN XY:

726992

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00260

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000832

Gnomad4 OTH exome

AF:

0.000779

GnomAD4 genome

AF:

0.000447

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000647

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000783

Hom.:

Bravo

AF:

0.000442

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000305

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000763

EpiControl

AF:

0.000712

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lipoyl transferase 1 deficiency

Pathogenic:8

Apr 12, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LIPT1 c.875C>G (p.Ser292X) results in a premature termination codon, predicted to disrupt the last 82 amino acids of the protein. The variant allele was found at a frequency of 0.00036 in 250868 control chromosomes. c.875C>G has been reported in the literature in an individual affected with Leigh disease with hypotonia, tetraparesis and steady aortic root dilatation and in a patient with abnormal development, seizures, and lactic acidemia, both in the compound heterozygous state (Soreze_2013, Ni_2019). Experimental evidence has shown the variant to impact LIPT1 function, including reduced lipoylation of PDHc and -KGDHc, and result in severely decreased PDHc and -KGDHc enzyme activities and abnormal pyruvate utilization by polarography (Soreze_2013, Ni_2019). The following publications have been ascertained in the context of this evaluation (PMID: 31042466, 24341803). ClinVar contains an entry for this variant (Variation ID: 285871). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This mutation has been previously reported as disease-causing and was found twice in our laboratory in trans with a missense variant: in an 8-year-old female with low pyruvate dehydrogenase activity, intellectual disability, hearing loss, hypotonia, epilepsy, microcephaly, failure to thrive, hepatopathy, anisocytosis, 2 deceased siblings similarly affected; in a 9-year-old female with spastic quadriparesis, single seizure, failure to thrive, scoliosis. Heterozygotes would be expected to be asymptomatic carriers. -

Jan 01, 2024

Daryl Scott Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM3, PP1 -

May 21, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0205 - Variant is predicted to result in a truncated protein with less than 1/3 of the protein affected. (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (101 heterozygotes, 0 homozygotes). (P) 0604 - Variant does not result in the loss of an established domain, motif, hotspot or informative constraint region. (N) 0704 – A comparable truncating variant has low previous evidence for pathogenicity, and has been observed in one family with fatal lactic acidosis (PMID: 27247813). (P) 0801 - Strong previous evidence of pathogenicity in multiple unrelated individuals with lactic acidosis and Leigh-like disease (ClinVar, PMID: 24341803, PMID: 31042466). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1001 - Strong functional evidence supporting abnormal protein function. Patient fibroblasts were found to have minimal residual protein and reduced lipoyation and mitochondrial respiratory chain protein activity. (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 10, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM3 -

Dec 17, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 18, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided

Pathogenic:3

Jan 28, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in one individual with Leigh syndrome and one individual with seizures, developmental delay and lactic acidemia; both individuals were compound heterozygous for another variant in LIPT1 (Soreze et al. 2013; Ni et al., 2019); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 82 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 28803783, 25326635, 24341803, 29681092, 31042466) -

Feb 10, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 16, 2024

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.Ser292*) in the LIPT1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 82 amino acid(s) of the LIPT1 protein. This variant is present in population databases (rs137891647, gnomAD 0.2%). This premature translational stop signal has been observed in individual(s) with clinical features of lipoyltransferase 1 deficiency (PMID: 24341803, 31042466; externalcommunication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 285871). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects LIPT1 function (PMID: 31042466). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Uncertain

0.98

Eigen

Uncertain

0.38

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.54

Vest4

0.21

GERP RS

4.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over