chr19-11107453-CAA-C

Position:

• chr19-11107453-CAA-C

Variant summary

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

The ENST00000558518.6(LDLR):​c.881_882del​(p.Lys294SerfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLR ENST00000558518.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 3.23

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 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 19-11107453-CAA-C is Pathogenic according to our data. Variant chr19-11107453-CAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 251499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11107453-CAA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.881_882del	p.Lys294SerfsTer6	frameshift_variant	6/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.881_882del	p.Lys294SerfsTer6	frameshift_variant	6/18	1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4

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) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed as heteozygous in at least five individuals with autosomal dominant familial hypercholesterolaemia (ClinVar, PMIDs: 11754108, 22698793). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	Aug 26, 2022	This sequence variant is a 2-nucleotide deletion (delAA) at coding positions 881 and 882 of the LDLR gene that generates an early termition codon 6 amino acids downstream from the frameshift introduced at codon 294. As it occurs in exon 6 of 18, this variant is predicted to generate a non-functiol allele through either the expression of a truncated protein or a loss of LDLR expression due to nonsense mediated decay. This is a previously reported variant (ClinVar) that has been observed in the literature in indiivudals with familial hypercholesterolemia (PMID: 22698793, 31653860). This variant is absent from control population datasets (gnomAD database 0 of ~250,000 alleles). Given that haploinsufficiency is a known mechanism of disease for LDLR, we consider this variant to be pathogenic. ACMG Criteria: PM2, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	- -

Homozygous familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 31, 2017

The p.Lys294SerfsX6 variant in LDLR (also described as p.Lys273SerfsX6 in the li terature) has been reported in at least 1 Czech individual with familial hyperch olesterolemia (FH; Kuhrova 2002, Tichy 2012). This variant has also been reporte d in ClinVar (Variation ID: 251499) and was absent from large population studies . It is predicted to cause a frameshift, which alters the protein?s amino acid s equence beginning at position 294 and leads to a premature termination codon 6 a mino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the LDLR gene is an establis hed disease mechanism in individuals with FH. In summary, the p.Lys294SerfsX6 va riant meets criteria to be classified as pathogenic for FH in an autosomal domin ant manner based upon the predicted impact to the protein and absence from the g eneral population. ACMG/AMP criteria applied: PVS1, PM2, PS4_Supporting. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2018

The c.881_882delAA pathogenic mutation, located in coding exon 6 of the LDLR gene, results from a deletion of two nucleotides at positions 881 to 882, causing a translational frameshift with a predicted alternate stop codon (p.K294Sfs*6). This mutation (also described as c.880_881delAA) was detected in a cohort of Czech patients with familial hypercholesterolemia (Kuhrová V et al. Hum. Mutat., 2001 Sep;18:253; Tichý L et al. Atherosclerosis, 2012 Aug;223:401-8). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, 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 11, 2022

This sequence change creates a premature translational stop signal (p.Lys294Serfs*6) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 251499). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 11754108). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs879254704; hg19: chr19-11218129;