chr2-99162325-AG-A

Position:

chr2-99162325-AG-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_145199.3(LIPT1):c.369del(p.Lys123AsnfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000913 in 1,613,298 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00073 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00093 ( 0 hom. )

Consequence

LIPT1
NM_145199.3 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2

Conservation

PhyloP100: 0.332

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 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. There are 4 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-99162325-AG-A is Pathogenic according to our data. Variant chr2-99162325-AG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 420362.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIPT1	NM_145199.3 linkuse as main transcript	c.369del	p.Lys123AsnfsTer8	frameshift_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.369del	p.Lys123AsnfsTer8	frameshift_variant	2/2		NM_145199.3	P1

Frequencies

GnomAD3 genomes

AF:

0.000729

AC:

111

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

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:

0.00146

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000576

AC:

144

AN:

249988

Hom.:

AF XY:

0.000547

AC XY:

AN XY:

135246

show subpopulations

Gnomad AFR exome

AF:

0.0000621

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.0000946

Gnomad NFE exome

AF:

0.00114

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000932

AC:

1362

AN:

1461064

Hom.:

Cov.:

AF XY:

0.000904

AC XY:

657

AN XY:

726894

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.000114

Gnomad4 NFE exome

AF:

0.00115

Gnomad4 OTH exome

AF:

0.000812

GnomAD4 genome

AF:

0.000729

AC:

111

AN:

152234

Hom.:

Cov.:

AF XY:

0.000632

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00146

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000304

Hom.:

Bravo

AF:

0.000631

EpiCase

AF:

0.00109

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Lipoyl transferase 1 deficiency

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 25, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as likely 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) 0204 - Variant is predicted to result in a truncated protein with more 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 (163 heterozygotes, 0 homozygotes). (P) 0507 - Identified variant type is not compatible with in silico predictions of pathogenicity. (N) 0600 - Variant is located in an annotated domain or motif. This truncation would result in the loss of part of the LpIa domain, including many active and catalytic sites (NCBI). (N) 0703 - Comparable variants have moderate previous evidence for pathogenicity. Several downstream truncating variants have been reported as pathogenic, with no functional evidence (PMID: 27247813, ClinVar). (P) 0803 - Low previous evidence of pathogenicity in unrelated individuals. Variant reported as likely pathogenic with no evidence (ClinVar). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 21, 2023	- -

not provided

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 18, 2023	Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 251 amino acids are lost and replaced with 7 incorrect amino acids (HGMD); Has not been previously published in association with LIPT1-related disorders to our knowledge; This variant is associated with the following publications: (PMID: 33531667) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 17, 2022	This sequence change creates a premature translational stop signal (p.Lys123Asnfs*8) in the LIPT1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 251 amino acid(s) of the LIPT1 protein. This variant is present in population databases (rs552120721, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with LIPT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 420362). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Hypotonia;C0029131:Abnormal optic nerve morphology;C1384666:Hearing impairment;C2315100:Failure to thrive;C4049796:Abnormal cardiovascular system morphology

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Jul 29, 2016

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 22, 2024

Variant summary: LIPT1 c.369delG (p.Lys123AsnfsX8) results in a premature termination codon and is predicted to cause a truncation of the encoded protein. Although the variant is not expected to cause nonsense mediated decay, the variant disrupts the last 251 amino acids of the LIPT1 protein, including those within the Biotinyl protein ligase (BPL) and lipoyl protein ligase (LPL), catalytic domains (IPR004143). A truncation downstream of this position has been classified as pathogenic within ClinVar (e.g. c.875C>G [p.Ser292Ter]). However, the variant allele was found at a frequency of 0.00091 in 1613298 control chromosomes in the gnomAD database. To our knowledge, no occurrence of c.369delG in individuals affected with Lipoyl Transferase 1 Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 420362). Based on the conflicting evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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