rs875989944

Positions:

• chr19-11129515-CTCCTCGTCT-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM4 PP5

The NM_000527.5(LDLR):​c.2397_2405del​(p.Val800_Leu802del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,534 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L798L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: LDLR NM_000527.5 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:16 U:5
• Conservation: PhyloP100: 7.51

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 8 uncertain in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000527.5.
• PP5: Variant 19-11129515-CTCCTCGTCT-C is Pathogenic according to our data. Variant chr19-11129515-CTCCTCGTCT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226394.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=5, Likely_pathogenic=7, Uncertain_significance=5}. Variant chr19-11129515-CTCCTCGTCT-C is described in Lovd as [Pathogenic]. Variant chr19-11129515-CTCCTCGTCT-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.2397_2405del	p.Val800_Leu802del	inframe_deletion	17/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.2397_2405del	p.Val800_Leu802del	inframe_deletion	17/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152142 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251148 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135824

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461392 Hom.: 0 AF XY: 0.0000165 AC XY: 12 AN XY: 727052

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152142 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74306

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:16 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:13 Uncertain:1

Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 13, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Jan 02, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	subjects mutated among 2600 FH index cases screened = 8 , family member = 1 with co-segregation / systematically associated with c.1690A>C, p.Asn564His -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 04, 2022	- -
Pathogenic, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	Jan 27, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Aug 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 07, 2021	_x000D_This variant was found in the same patient as NM_000527.5:c.1690A>C. Criteria applied: PS3_MOD, PS4, PM2_SUP, PM4, PP4 -

not provided Pathogenic:3 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Functional studies suggest p.(N564H) in cis with LDLR p.(V800_L802del) (also reported as p.(S820_N22del) due to alternate nomenclature) results in an affect on the enzyme function (PMID: 9143924, 12442279); In-frame deletion of 3 amino acids in a non-repeat region; In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22390909, 30795984, 31447099, 9147888, 9143924, 12442279, 33740630, 32770674, 34456049, 32719484) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	LDLR: PM2, PM4, PS4:Moderate, PS3:Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 28, 2021

Variant summary: LDLR c.2397_2405delCGTCTTCCT (p.Val800_Leu802del) results in an in-frame deletion that is predicted to remove 3 amino acids from the encoded protein. The variant allele was found at a frequency of 8e-06 in 251148 control chromosomes (i.e. 2 alleles in the European (non-Finnish) subpopulation) in the gnomAD database (v2.1 dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.2397_2405delCGTCTTCCT (aka. 2393del9), has been reported in the literature in several individuals affected with Familial Hypercholesterolemia (e.g. Jensen_1996, Castillo_2002, Fouchier_2001, Umans-Eckenhausen_2002, Kusters_2011, Sjouke_2016, Martin-Campos_2018, Leren_2021), however in almost all of these cases the variant reportedly occurred together with c.1690A>C (p.Asn564His) on the same chromosome (i.e. in cis), as a complex allele. These reports therefore do not provide unequivocal conclusions about association of the variant in isolation with Familial Hypercholesterolemia. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that when this variant was expressed in isolation, it had a mild effect on LDLR function (~75-85% activity of the normal; Jensen_1996), however, when it was part of the complex allele, i.e. occurring together with p.Asn564His in the same protein, the LDLR receptor function was markedly reduced (to ~20-25% of the normal; Jensen_1996, Castillo_2002). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=1), likely pathogenic (n=4), or pathogenic (n=4). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2022

The c.2397_2405delCGTCTTCCT variant (also known as p.V800_L802del) is located in coding exon 17 of the LDLR gene. This variant results from an in-frame CGTCTTCCT deletion at nucleotide positions 2397 to 2405. This results in the in-frame deletion of a at codon 800. This alteration has been reported in familial hypercholesterolemia (FH) cohorts and is often described on the same chromosome, or in cis, with the alteration, p.N564H (Alonso R et al. J Clin Lipidol Apr;10:953-961; Lombardi P et al. Clin Genet, 1996 Dec;50:525-6; Jensen HK et al. Atherosclerosis, 1999 Oct;146:337-44; Ebhardt M et al. Hum Mutat, 1999;13:257; Fouchier SW et al. Hum Genet, 2001 Dec;109:602-15; Mozas P et al. Hum Mutat, 2004 Aug;24:187; Martín-Campos JM et al. J Clin Lipidol Sep;12:1452-1462). This alteration was also detected in a cohort of 29,906 healthy individuals who underwent multigene panel testing (Grzymski JJ et al. Nat Med, 2020 08;26:1235-1239). This amino acid position ranges from not well to poorly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Familial hypercholesterolemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 16, 2023

This variant, c.2397_2405del, results in the deletion of 3 amino acid(s) of the LDLR protein (p.Val800_Leu802del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has been observed in individual(s) with familial hypercholesterolemia. This variant is frequently in cis with p.Asn564His and may represent a single allele (PMID: 9143924, 9147888, 10090484, 12442279, 30795984). This variant is also known as 2393del9. ClinVar contains an entry for this variant (Variation ID: 226394). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on LDLR function (PMID: 9143924). 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. -

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: rs875989944; hg19: chr19-11240191;