rs875989896

Positions:

• chr19-11102785-TCG-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000527.5(LDLR):​c.313_313+1delCG​(p.Lys107fs) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,102 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LDLR NM_000527.5 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 8.10

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]

LDLR (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-11102785-TCG-T is Pathogenic according to our data. Variant chr19-11102785-TCG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 226316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11102785-TCG-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.313_313+1delCG	p.Lys107fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	3/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.313_313+1delCG	p.Lys107fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	3/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461102 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 726852

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	Updated according to ClinGen VCEP Guidelines (2022) for LDLR variant classification in FH (PMID: 34906454). This frameshift mutation is estimated to generate truncated protein products deprived of most of their functional domains (PVS1). In addition, this deletion abolishes the canonical donor splice site of intron 3, without potentially creating any alternate donor splice site in close vicinity (PP3). It was shown by in-vitro studies (PS3 moderate) to abolish protein expression in homozygous carriers (FH Lille Allele). Mutation recurrently causing FH diagnosed by validated clinical criteria reported in multiple Disease Specific Databases for several decades (PS4) . Absent from Large General Population Databases (PM2 Strong). More than 10 index cases from the Lille registry had a clinical scoring of Definite FH (DLCN Score >8). This clinical scoring level is highly specific (90%) for a carrier status of a pathogenic LDLR mutation causative of FH (PP4 Strong). -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Pathogenic, criteria provided, single submitter	curation;literature only	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -
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 = 2 , family members = 2 -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 02, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Jul 09, 2008	- -
Pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

Homozygous familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 11, 2019

The c.313_313+1delCG variant in LDLR has been reported in 2 individuals with hypercholesterolemia (Hobbs 1992, Hooper 2012). It was absent from large population studies. This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. An in vitro study supports an impact on splicing (Hobbs 1992). Loss of function of the LDLR gene is an established disease mechanism in autosomal dominant familial hypercholesterolemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant familial hypercholesterolemia. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2022

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect as cell cultures from a homozygous patient show 2-5% residual LDL receptor activity (Hobbs et al., 1992); Canonical splice site variant expected to result in aberrant splicing; Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); Also known as FH Lille; This variant is associated with the following publications: (PMID: 1301956, 33087929, 22883975) -

Familial hypercholesterolemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jan 22, 2020

The c.313_313+1delCG variant in LDLR has been reported in 1 Australian and 1 French individual with familial hypercholesterolemia (PMID: 22883975, 1301956), and was absent from large population studies. This variant has also been reported in ClinVar as pathogenic (Variation ID: 226316). In vitro functional studies provide some evidence that the c.313_313+1delCG variant may slightly impact protein function (PMID: 1301956). However, these types of assays may not accurately represent biological function. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence, deletes the last base of the exon inducing a frameshift, and is predicted to cause altered splicing leading to an abnormal or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in familial hypercholesterolemia. There is an in-frame cryptic splice site within 6 basepairs of the intron-exon boundary that could result in a rescued transcript and may maintain function of LDLR. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3_supporting, PS4_supporting, PVS1_moderate, PM2 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.41		Position offset: -49
DS_DL_spliceai		0.99		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs875989896; hg19: chr19-11213461;