rs875989905

Variant names:

• chr19-11105562-GC-G
• rs875989905
• NM_000527.5:c.660delC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000527.5(LDLR):​c.660delC​(p.Asp221ThrfsTer44) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P220P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR NM_000527.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: -1.25
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 19-11105562-GC-G is Pathogenic according to our data. Variant chr19-11105562-GC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 226330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.660delC	p.Asp221ThrfsTer44	frameshift_variant	Exon 4 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.660delC	p.Asp221ThrfsTer44	frameshift_variant	Exon 4 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4

-

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

May 11, 2019

Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 05, 2014

Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial hypercholesterolemia Pathogenic:3

Feb 10, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Asp221Thrfs*44) 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 (ExAC no frequency). This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 9678702, 11139254, 22883975, 11462246, 15556094). This variant is also known as P199fsX243, 657delC. ClinVar contains an entry for this variant (Variation ID: 226330). -

Jan 26, 2024

GENinCode PLC

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.660del p.(Asp221ThrfsTer44) variant in LDLR is a frameshift variant predicted to create a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in >10 FH patients meeting clinical criteria, including patients where secondary causes of high cholesterol were excluded (PS4_STRONG, PP4_SUPPORTING; PMIDs 9678702, 11139254, 11462246, 15556094, 17539906, 26875521, https://doi.org/10.1177/1474651412466272). This variant was also observed in the compound heterozygous state with a second pathogenic LDLR variant in an individual with a homozygous FH phenotype, where variants were confirmed in trans (PM3_MODERATE; PMID:22883975). The variant is absent from gnomAD v4.1.0 (PM2_MODERATE). Based on the evidence listed above, we have classified this variant as Pathogenic. -

Dec 07, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:1

Dec 14, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 34037665, 9678702) -

Cardiovascular phenotype Pathogenic:1

Dec 13, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.660delC (p.D221Tfs*44) alteration, located in exon 4 (coding exon 4) of the LDLR gene, consists of a deletion of one nucleotide at position 660, causing a translational frameshift with a predicted alternate stop codon after 44 amino acids. Frameshift alterations are typically deleterious in nature (Richards, 2015). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This mutation (also described as c.657delC) has been reported in numerous familial hypercholesterolemia (FH) cohorts from a variety of ethnic backgrounds (Lee, 1998; Bochmann, 2001; Laurie, 2004; Bamimore, 2015; Hu, 2016). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.2
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs875989905; hg19: chr19-11216238;