19-42401821-CCCCCCGCAGCCCCCGTCTA-C

Position:

• chr19-42401821-CCCCCCGCAGCCCCCGTCTA-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_005357.4(LIPE):​c.3203_3221del​(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:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00047 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: LIPE NM_005357.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.87

Genes affected

LIPE (HGNC:6621): (lipase E, hormone sensitive type) The protein encoded by this gene has a long and a short form, generated by use of alternative translational start codons. The long form is expressed in steroidogenic tissues such as testis, where it converts cholesteryl esters to free cholesterol for steroid hormone production. The short form is expressed in adipose tissue, among others, where it hydrolyzes stored triglycerides to free fatty acids. [provided by RefSeq, Jul 2008]

LIPE-AS1 (HGNC:48589): (LIPE antisense RNA 1)

LOC101930071 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon NOT found. This looks like a Nonstop Mediated Decay case. LoF is a known mechanism of disease.
• PP5: Variant 19-42401821-CCCCCCGCAGCCCCCGTCTA-C is Pathogenic according to our data. Variant chr19-42401821-CCCCCCGCAGCCCCCGTCTA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 155901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIPE	NM_005357.4	c.3203_3221del	p.Val1068GlyfsTer102	frameshift_variant	10/10	ENST00000244289.9
LIPE-AS1	NR_073180.1	n.77+4616_77+4634del		intron_variant, non_coding_transcript_variant
LOC101930071	NR_126041.1	n.97+4616_97+4634del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIPE	ENST00000244289.9	c.3203_3221del	p.Val1068GlyfsTer102	frameshift_variant	10/10	1	NM_005357.4	P1
LIPE-AS1	ENST00000594624.7	n.66+4616_66+4634del		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.000567 AC: 86 AN: 151760 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00289

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.000837

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000442

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000798 AC: 67 AN: 83980 Hom.: 1 AF XY: 0.000979 AC XY: 45 AN XY: 45956

Gnomad AFR exome AF: 0.000919

Gnomad AMR exome AF: 0.000671

Gnomad ASJ exome AF: 0.00265

Gnomad EAS exome AF: 0.000286

Gnomad SAS exome AF: 0.00116

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000759

Gnomad OTH exome AF: 0.00124

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000467 AC: 620 AN: 1327478 Hom.: 1 AF XY: 0.000463 AC XY: 302 AN XY: 652232

Gnomad4 AFR exome AF: 0.000395

Gnomad4 AMR exome AF: 0.000491

Gnomad4 ASJ exome AF: 0.00152

Gnomad4 EAS exome AF: 0.000269

Gnomad4 SAS exome AF: 0.000658

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000458

Gnomad4 OTH exome AF: 0.000417

GnomAD4 genome AF: 0.000566 AC: 86 AN: 151870 Hom.: 0 Cov.: 30 AF XY: 0.000526 AC XY: 39 AN XY: 74180

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00289

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.000838

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000442

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000622 Hom.: 1

Bravo AF: 0.000676

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

LIPE-related familial partial lipodystrophy Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 02, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Mar 24, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 12, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 01, 2023	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. -

LIPE-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 20, 2024

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: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587777699; hg19: chr19-42905973;