19-42401821-CCCCCCGCAGCCCCCGTCTA-C
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_ModeratePP5_Very_Strong
The NM_005357.4(LIPE):c.3203_3221delTAGACGGGGGCTGCGGGGG(p.Val1068GlyfsTer102) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000566 in 151,870 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_005357.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000567 AC: 86AN: 151760Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.000798 AC: 67AN: 83980Hom.: 1 AF XY: 0.000979 AC XY: 45AN XY: 45956
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000467 AC: 620AN: 1327478Hom.: 1 AF XY: 0.000463 AC XY: 302AN XY: 652232
GnomAD4 genome AF: 0.000566 AC: 86AN: 151870Hom.: 0 Cov.: 30 AF XY: 0.000526 AC XY: 39AN XY: 74180
ClinVar
Submissions by phenotype
LIPE-related familial partial lipodystrophy Pathogenic:4
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Variant summary: LIPE c.3203_3221del19 (p.Val1068GlyfsX102) causes a frameshift which results in an extension of the protein and is not expected to undergo nonsense mediated decay. The variant allele was found at a frequency of 0.00048 in 1479348 control chromosomes in the gnomAD database, including 1 homozygote. Notably, it is found at a frequency of 0.024 within individuals of Amish ancestry. c.3203_3221del19 has been reported in the literature in the homozygous state in four siblings with clinical features of LIPE-Related Familial Partial Lipodystrophy from an Old Order Amish family where the variant primarily segregated with the disease phenotype amongst a total of ten siblings (Albert_2014). The variant has also been reported either in the heterozygous state or as an uninformative genotype in at least two other individuals with low HDL cholesterol/dyslipidemia who underwent WES/multigene panel testing (e.g. Dron_2020, Dong_2022). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Albert_2014). In vitro, the variant was not found to significantly affect mRNA expression, but resulted in reduced protein levels. Additionally, in subcutaneous abdominal adipocytes from homozygous individuals, no protein was detected and triglyceride lipase activity and cholesterol ester hydrolase activity were reduced compared to wild type individuals and heterozygous carriers. The following publications have been ascertained in the context of this evaluation (PMID: 24848981, 35460704, 32041611). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
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LIPE-related disorder Pathogenic:1
The LIPE c.3203_3221del19 variant is predicted to result in a frameshift and premature protein termination (p.Val1068Glyfs*102). This variant has been reported in the homozygous state in four siblings from an Amish community with partial lipodystrophy (p.V767Gfs*102 in Albert et al. 2014. PubMed ID: 24848981). Albert et al. also found that heterozygous individuals did not display the same adipose-tissue dysfunction as homozygous individuals; however, they did present with a range of features including dyslipidemia, hepatic steatosis, and diabetes (Albert et al. 2014. PubMed ID: 24848981). In addition, other studies have suggested that this variant leads to an increased risk of hypertriglyceridemia and other types of dyslipidemia when found in the heterozygous state (Table S2 in Deshotels et al. 2022. PubMed ID: 36325899; Table S4 in Dron et al. 2020. PubMed ID: 32041611). Familial segregation data and biochemical studies support its pathogenicity (Albert et al. 2014. PubMed ID: 24848981). This variant is reported in 0.27% of alleles in individuals of Ashkenazi Jewish descent in gnomAD; however, the quality of the data at this position is questionable and should be interpreted with caution. Frameshift variants in LIPE are expected to be pathogenic. This variant is interpreted as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at