2-99162249-C-G

Position:

chr2-99162249-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_145199.3(LIPT1):c.292C>G(p.Arg98Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,613,220 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R98Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

LIPT1
NM_145199.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 1.14

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:

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 Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

PP5

Variant 2-99162249-C-G is Pathogenic according to our data. Variant chr2-99162249-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 189836.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIPT1	NM_145199.3 linkuse as main transcript	c.292C>G	p.Arg98Gly	missense_variant	2/2	ENST00000651691.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIPT1	ENST00000651691.1 linkuse as main transcript	c.292C>G	p.Arg98Gly	missense_variant	2/2		NM_145199.3	P1

Frequencies

GnomAD3 genomes

AF:

0.000119

AC:

AN:

151876

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000116

AC:

AN:

249996

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

135248

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000230

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000183

AC:

267

AN:

1461228

Hom.:

Cov.:

AF XY:

0.000187

AC XY:

136

AN XY:

726926

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000229

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000118

AC:

AN:

151992

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.000207

Hom.:

Bravo

AF:

0.0000945

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 05, 2022	The LIPT1 c.292C>G (p.Arg98Gly) missense variant results in the substitution of arginine at amino acid position 98 with glycine.The c.292C>G variant is reported in a compound heterozygous state in two affected individuals in the literature, in both instances, in trans with the p.Ser71Phe variant (PMID: 24256811; PMID: 34440436). Normal LIPT1 protein levels are reported in patient liver cells, but transfection of patient fibroblasts with the c.292C>G variant did not restore lipoylation of mitochondrial proteins, PDHC activity, or increase the oxidation rate of pyruvate or leucine, suggesting a loss of function consequence. Additionally, the Arg98 residue is conserved and structural modelling suggests that it is involved in lipoic acid binding (PMID: 24256811; PMID: 17570395). The c.292C>G variant is reported at a frequency of 0.000241 in the European (non-Finnish) population of the Genome Aggregation Database (version 2.1.1). Based on the available evidence, c.292C>G (p.Arg98Gly) variant is classified as likely pathogenic for lipoyltransferase 1 deficiency. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 2022	Published functional studies in patient fibroblasts demonstrate that transfection of wildtype LIPT1 enzyme rescued PDHC complex activity, whereas transfection of R98G LIPT1 enzyme did not (Tort et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24256811, 29681092, 27247813, 26740555, 28719003, 26633542) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 25, 2022	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 98 of the LIPT1 protein (p.Arg98Gly). This variant is present in population databases (rs137973334, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of lipoyltransferase 1 deficiency (PMID: 24256811). ClinVar contains an entry for this variant (Variation ID: 189836). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LIPT1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Lipoyl transferase 1 deficiency

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.49

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.74

D;D;.;D;.

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.90

D;.;D;D;D

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.96

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.2

H;H;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-6.6

D;D;D;D;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;D;.;.;.

Vest4

0.99

MVP

0.86

ClinPred

0.96

GERP RS

4.0

Varity_R

0.88

gMVP

0.94

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