chr2-99162088-A-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_145199.3(LIPT1):āc.131A>Gā(p.Asn44Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,080 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
Consequence
NM_145199.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LIPT1 | ENST00000651691.1 | c.131A>G | p.Asn44Ser | missense_variant | Exon 2 of 2 | NM_145199.3 | ENSP00000498546.1 | |||
ENSG00000273155 | ENST00000410042.1 | c.-28+5662A>G | intron_variant | Intron 2 of 5 | 2 | ENSP00000387111.1 | ||||
ENSG00000241962 | ENST00000424491.5 | n.63+11569A>G | intron_variant | Intron 4 of 13 | 2 | ENSP00000390891.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152214Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251382Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135860
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461866Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 727228
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152214Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74362
ClinVar
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
The c.131A>G (p.N44S) alteration is located in exon 3 (coding exon 1) of the LIPT1 gene. This alteration results from an A to G substitution at nucleotide position 131, causing the asparagine (N) at amino acid position 44 to be replaced by a serine (S). Based on data from gnomAD, the G allele has an overall frequency of <0.01% (1/251382) total alleles studied. This alteration was detected in trans with a frameshift alteration in LIPT1 in an individual with abnormal development, seizures, lactic acidemia, hypotonia, along with 70% reduction in pyruvate dehydrogenase (PDH) activity in skin fibroblasts and low normal alpha dehydrogenase (AKGDH) activity (Ni, 2019). This amino acid position is highly conserved in available vertebrate species. In vitro and in vivo experimental studies show that this alteration led to abnormal lipoylation and impaired activation of PDH and AKGDH (Ni, 2019). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -
not provided Pathogenic:1
The LIPT1 c.131A>G (p.Asn44Ser) missense variant results in the substitution of asparagine at amino acid position 44 with serine. The c.131A>G variant is reported compound heterozygous state with a nonsense variant in one affected individual in the literature, a child with abnormal development, seizures, and lactic acidemia and with two similarly affected siblings who were not genotyped (PMID: 31042466). Transfection of patient fibroblasts with the c.131A>G variant resulted in partial restoration of lipoylation and PDHA1 phosphorylation compare to transfection with the WT allele, suggesting it is hypomorphic allele (PMID: 31042466). A mouse model homozygous for the c.131A>G variant was not viable, but fetuses showed developmental and biochemical features consistent with the human phenotype (PMID: 31042466; PMID: 35388219). Additionally, the Asn44 residue is conserved and structural modelling suggests that it interacts with other conserved residues in the N-terminal domain (PMID: 31042466). The p.Asn44Ser variant is reported in one allele at a frequency of 0.00001470 in the European (non-Finnish) population of the Genome Aggregation Database (version 3.1.2). Based on the available evidence, c.131A>G (p.Asn44Ser) variant is classified as likely pathogenic for lipoyltransferase 1 deficiency. -
Lipoyl transferase 1 deficiency Uncertain:1
Likely pathogenicity based on finding it twice in our laboratory in trans with a nonsense variant: in an 8-year-old female with low pyruvate dehydrogenase activity, intellectual disability, hearing loss, hypotoniea, 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 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at