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.369delG(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
Consequence
NM_145199.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LIPT1 | ENST00000651691.1 | c.369delG | p.Lys123AsnfsTer8 | frameshift_variant | Exon 2 of 2 | NM_145199.3 | ENSP00000498546.1 | |||
ENSG00000273155 | ENST00000410042.1 | c.-28+5900delG | intron_variant | Intron 2 of 5 | 2 | ENSP00000387111.1 | ||||
ENSG00000241962 | ENST00000424491.5 | n.63+11807delG | intron_variant | Intron 4 of 13 | 2 | ENSP00000390891.1 |
Frequencies
GnomAD3 genomes AF: 0.000729 AC: 111AN: 152234Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000576 AC: 144AN: 249988Hom.: 0 AF XY: 0.000547 AC XY: 74AN XY: 135246
GnomAD4 exome AF: 0.000932 AC: 1362AN: 1461064Hom.: 0 Cov.: 32 AF XY: 0.000904 AC XY: 657AN XY: 726894
GnomAD4 genome AF: 0.000729 AC: 111AN: 152234Hom.: 0 Cov.: 31 AF XY: 0.000632 AC XY: 47AN XY: 74386
ClinVar
Submissions by phenotype
Lipoyl transferase 1 deficiency Pathogenic:2
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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:1Uncertain:1
Has not been previously published in association with LIPT1-related disorders to our knowledge; Frameshift variant predicted to result in abnormal protein length as the last 251 amino acid(s) are replaced with 7 different amino acid(s), and other similar variants have been reported in HGMD; This variant is associated with the following publications: (PMID: 33531667) -
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
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not specified Uncertain:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at