chr2-99162832-C-G
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_145199.3(LIPT1):āc.875C>Gā(p.Ser292Ter) 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 (ā ā ).
Frequency
Genomes: š 0.00045 ( 0 hom., cov: 32)
Exomes š: 0.00072 ( 0 hom. )
Consequence
LIPT1
NM_145199.3 stop_gained
NM_145199.3 stop_gained
Scores
2
2
3
Clinical Significance
Conservation
PhyloP100: 1.86
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LIPT1 | NM_145199.3 | c.875C>G | p.Ser292Ter | stop_gained | 2/2 | ENST00000651691.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LIPT1 | ENST00000651691.1 | c.875C>G | p.Ser292Ter | stop_gained | 2/2 | NM_145199.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000447 AC: 68AN: 152130Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000363 AC: 91AN: 250868Hom.: 0 AF XY: 0.000346 AC XY: 47AN XY: 135656
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GnomAD4 exome AF: 0.000715 AC: 1045AN: 1461412Hom.: 0 Cov.: 34 AF XY: 0.000714 AC XY: 519AN XY: 726992
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GnomAD4 genome AF: 0.000447 AC: 68AN: 152248Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28AN XY: 74452
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Lipoyl transferase 1 deficiency Pathogenic:6
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 12, 2024 | 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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 17, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2017 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | May 10, 2023 | PVS1, PM3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 21, 2020 | 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 ā 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 - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 24, 2023 | 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 protein 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 10, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 28, 2023 | 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) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
D
MutationTaster
Benign
D;D;D;D;D;D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at