rs875989888

Positions:

• chr19-11089550-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000527.5(LDLR):​c.6del​(p.Trp4_?2) variant causes a frameshift, start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,459,854 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: LDLR NM_000527.5 frameshift, start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 2.42

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-AS1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 1048 pathogenic variants in the truncated region.
• PS1: Another start lost variant in NM_000527.5 (LDLR) was described as [Likely_pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-11089550-TG-T is Pathogenic according to our data. Variant chr19-11089550-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 226303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11089550-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.6del	p.Trp4_?2	frameshift_variant, start_lost	1/18	ENST00000558518.6	NP_000518.1
LDLR-AS1	NR_163945.1	n.109del		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.6del	p.Trp4_?2	frameshift_variant, start_lost	1/18	1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1459854 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 726250

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 18, 2022	- -
Pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	Jan 22, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Aug 11, 2011	- -
Pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

Familial hypercholesterolemia Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 21, 2022	Variant summary: LDLR c.6delG (p.Trp4GlyfsX202) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 248678 control chromosomes (gnomAD). c.6delG has been reported in the literature in individuals affected with Familial Hypercholesterolemia (examples: Day_1997, Taylor_2007, and Hooper_2012). These data indicate that the variant is likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 13, 2018	Pathogenic variant based on current evidence: This variant deletes one nucleotide after the translation start codon of the LDLR gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with familial hypercholesterolemia in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Loss-of-function truncation variants in the LDLR gene are known to be pathogenic (PMID: 20809525). Based on available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 14, 2023	This sequence change creates a premature translational stop signal (p.Trp4Glyfs*202) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (FH) (PMID: 24075752). ClinVar contains an entry for this variant (Variation ID: 226303). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 04, 2020	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 13, 2021	This frameshift variant is predicted to cause the premature termination of LDLR protein synthesis. It has been reported in individuals affected with familial hypercholesterolemia in the published literature (PMID: 31345425 (2019), 9259195 (1997)). Therefore, the variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	The LDLR c.6del; p.Trp4Glyfs variant (rs875989888; ClinVar Variation ID: 226303) is reported in the literature in multiple individuals affected with familial hypercholesterolemia (FH; selected references: Day 1997, Sturm 2021, Taylor, 2007). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant causes a frameshift by deletinga single nucleotide in exon 1, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, several up- and downstream truncating variants have been described in individuals with FH and are considered pathogenic (Hobbs 1992). Based on available information, this variant is considered to be pathogenic. References: Day IN et al. Spectrum of LDL receptor gene mutations in heterozygous familial hypercholesterolemia. Hum Mutat. 1997;10(2):116-27. doi: 10.1002/(SICI)1098-1004(1997)10:2<116::AID-HUMU4>3.0.CO;2-I. PMID: 9259195. Hobbs HH et al. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat. 1992;1(6):445-66. PMID: 1301956. Sturm AC et al. Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis. JAMA Cardiol. 2021 Aug 1;6(8):902-909. PMID: 34037665 Taylor A et al. Multiplex ARMS analysis to detect 13 common mutations in familial hypercholesterolaemia. Clin Genet. 2007 Jun;71(6):561-8. PMID: 17539906. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2024	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28964736, 22883975, 17539906, 24075752, 34037665, 9259195) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2022

The c.6delG pathogenic mutation, located in coding exon 1 of the LDLR gene, results from a deletion of one nucleotide at position 6, causing a translational frameshift with a predicted alternate stop codon (p.W4Gfs*202). This alteration has been previously reported in familial hypercholesterolemia cohorts (Hooper AJ et al. Atherosclerosis. 2012;224(2):430-4; Faiz F et al. Atherosclerosis. 2013;230(2):249-55). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

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: rs875989888; hg19: chr19-11200226;