2-99162325-AG-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2
• Conservation: PhyloP100: 0.332

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]

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]

ACMG classification

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	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	c.369del	p.Lys123AsnfsTer8	frameshift_variant	2/2		NM_145199.3	P1

Frequencies

GnomAD3 genomes AF: 0.000729 AC: 111 AN: 152234 Hom.: 0 Cov.: 31

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.: 0 AF XY: 0.000547 AC XY: 74 AN XY: 135246

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.: 0 Cov.: 32 AF XY: 0.000904 AC XY: 657 AN XY: 726894

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.: 0 Cov.: 31 AF XY: 0.000632 AC XY: 47 AN XY: 74386

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.: 0

Bravo AF: 0.000631

EpiCase AF: 0.00109

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lipoyl transferase 1 deficiency Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 21, 2023	- -
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 -

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	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. -
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) -

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

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

Other links and lift over

dbSNP: rs552120721; hg19: chr2-99778788; COSMIC: COSV60739554; COSMIC: COSV60739554;