rs875989897

Positions:

• chr19-11102787-G-GT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001406861.1(LDLR):​c.573dupT​(p.Lys192fs) variant causes a frameshift, stop gained change. The variant allele was found at a frequency of 0.00000274 in 1,460,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: LDLR NM_001406861.1 frameshift, stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 5.04

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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0575 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-11102787-G-GT is Pathogenic according to our data. Variant chr19-11102787-G-GT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 226317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.313+2dupT		splice_region_variant, intron_variant		ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.313+2dupT		splice_region_variant, intron_variant		1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251424 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460880 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726744

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

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:8

Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Likely pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Jul 04, 2013	- -
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	subject mutated among 2600 FH index cases screened = 1, family member=1 -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with both familial hypercholesterolaemia (MIM#143890) and LDL cholesterol level QTL2 (MIM#143890). (I) 0108 - This gene is associated with both recessive and dominant disease. Individuals with biallelic pathogenic variants are reported to have an earlier and more severe onset of disease (GeneReviews). (I) 0112 - The condition associated with this gene has incomplete penetrance (GeneReviews). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This variant has been shown to cause exon 3 skipping, resulting in an in-frame deletion/insertion, p.(Leu64_Pro105delinsSer) (PMID: 21990180). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (1 heterozygote, 0 homozygotes). (SP) 0600 - Variant is predicted to result in a loss of the second calcium-binding repeat (PMID: 21990180). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic/likely pathogenic (ClinVar) and in individuals with familial hypercholesterolaemia including heterozygotes (PMIDs: 15241806, 21990180, 27784735). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional studies using patient lymphocytes showed this variant causes reduced LDL binding and uptake (PMID: 21990180). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2018

The c.313+2dupT intronic pathogenic mutation, results from a duplication of a T nucleotide two nucleotide positions after coding exon 3 of the LDLR gene. This alteration has been detected as homozgyous in multiple individuals with clinically confirmed homozygous familial hypercholesterolemia (HoFH) (Sánchez-Hernández RM et al. Circ Cardiovasc Genet, 2016 Dec;9:504-510; Alonso R et al. J Clin Lipidol Apr;10:953-961) and as heterozygous in multiple individuals with familial hypercholesterolemia (FH) (Bañares VG et al. J Clin Lipidol Feb;11:524-531; Gabová D et al. Physiol Res, 2017 Mar;66:75-84; Mozas P et al. Hum. Mutat., 2004 Aug;24:187). In one functional study, authors showed that this mutation impacts ligand binding and results in the skipping of in-frame exon 3 at the mRNA level (Etxebarria A et al. Hum. Mutat., 2012 Jan;33:232-43). In addition, a different alteration with the same molecular splicing impact, c.313+6T>C, has been detected in individuals with FH and has been shown at the mRNA level to induce exon 3 skipping (Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42). (Bourbon M et al. J. Med. Genet., 2009 May;46:352-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

This sequence change falls in intron 3 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has been observed in individuals with familial hypercholesterolemia (PMID: 15241806, 21990180). ClinVar contains an entry for this variant (Variation ID: 226317). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 21990180). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.82		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.82		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: rs875989897; hg19: chr19-11213463;