chr19-11129597-AC-A

Variant names:

• chr19-11129597-AC-A
• rs747344293
• NM_000527.5:c.2478delC

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.2478delC​(p.Val827SerfsTer102) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: -0.0920

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 19-11129597-AC-A is Pathogenic according to our data. Variant chr19-11129597-AC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 252342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11129597-AC-A is described in Lovd as [Pathogenic]. Variant chr19-11129597-AC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.2478delC	p.Val827SerfsTer102	frameshift_variant	Exon 17 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2478delC	p.Val827SerfsTer102	frameshift_variant	Exon 17 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461848 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Sep 13, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 1 nucleotide in exon 17 of the LDLR gene, causing a frameshift and addition of 102 new amino acids before introducing a stop codon. This results in a protein product that is 67 amino acids longer than the normal protein product. This variant is expected to disrupt a portion of the C-terminal cytoplasmic domain, which is required for receptor internalization of the LDLR protein function (PMID: 2088165 , 22509010). An in vitro functional study using heterologous transfected CHO cells has shown that this variant causes either no detectable LDLR protein, or low levels of LDLR protein that is unable to bind the LDL ligand (PMID: 7903864). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 7903864, 29095814, 29353225, 34037665; ClinVar SCV000782943.1). It has been shown that this variant segregates with disease in two affected individuals in one family (PMID: 7903864). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation;literature only

- -

Jan 02, 2018

Robarts Research Institute, Western University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Feb 23, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2478delC pathogenic variant in the LDLR gene was paternally inherited in a Chinese child with severe familial hypercholesterolemia and a second maternally inherited variant in the LDLR gene; of note, the heterozygous father was reported to have elevated cholesterol (Sun et al., 1994). This variant causes a shift in reading frame starting at codon valine (Val) 827, changing it to a serine (Ser), and creating a premature stop codon at position 102 of the new reading frame, denoted p.Val827SerfsX102. This pathogenic variant is located in the penultimate exon and is predicted to result in an abnormal protein product with the last 34 amino acid residues replaced by 101 incorrect amino acid residues. Functional studies show that the c.2478delC variant results in either no detectable LDLR protein, or low levels of LDLR protein that is unable to bind the LDL ligand (Sun et al., 1994). Other frameshift variants in the LDLR gene have been reported in Human Gene Mutation Database in association with FH (Stenson et al., 2014), including a different downstream frameshift variant (c.2509delC) predicted to use the same termination codon as the c.2478delC variant. Furthermore, the c.2478delC variant has not been observed in large population cohorts (Lek et al., 2016). -

Cardiovascular phenotype Pathogenic:1

Oct 12, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2478delC (p.V827Sfs*102) alteration, located in exon 17 (coding exon 17) of the LDLR gene, consists of a deletion of one nucleotide at position 2478, causing a translational frameshift with a predicted alternate stop codon after 102 amino acids. This alteration occurs at the 3' terminus of theLDLR gene, is not expected to trigger nonsense-mediated mRNAdecay and results in the elongation of the protein by 67 amino acids. This frameshift impacts the last 34 amino acids(~4%) of the native protein. However, frameshifts are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration, referred to as a 1-bp deletion in codon 805, was reported in a family with familial hypercholesterolemia and in vitro studies suggested that it would affect LDLR protein expression or stability (Sun, 1994). Based on the available evidence, this alteration is classified as pathogenic. -

Familial hypercholesterolemia Pathogenic:1

Nov 04, 2022

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 variant disrupts a region of the LDLR protein in which other variant(s) (p.Ser849*) have been determined to be pathogenic (PMID: 2088165, 11933210, 22509010, 26892515). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This sequence change creates a premature translational stop signal (p.Val827Serfs*102) in the LDLR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 34 amino acid(s) of the LDLR protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hypercholesterolemia (PMID: 7903864). ClinVar contains an entry for this variant (Variation ID: 252342). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects LDLR function (PMID: 7903864). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs747344293; hg19: chr19-11240273;