rs1057516135

Positions:

• chr19-11105371-CA-C

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.467del​(p.Asn156ThrfsTer50) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR NM_000527.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 6.24

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 19-11105371-CA-C is Pathogenic according to our data. Variant chr19-11105371-CA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 369873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.467del	p.Asn156ThrfsTer50	frameshift_variant	4/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.467del	p.Asn156ThrfsTer50	frameshift_variant	4/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	May 24, 2017	The c.467del (p.Asn156Thrfs*50) variant in the LDLR gene has not been reported in the ExAC database not has been observed in our internal database. This variant has been reported in ClinVar as a likely pathogenic variant (RCV000408765.1) based on a publication [PMID 27765764] . However, the variant was not observed in this report and it is thus considered a novel variant by our criteria. This 1 bp deletion in exon 4 results in a frameshift and the creation of a premature stop codon, 50 amino acid downstream of Asn156. This variant is predicted to result in a loss of function of the protein. This variant is thus classified as pathogenic. -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -

Familial hypercholesterolemia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 10, 2023	This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn156Thrfs*50) 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 has not been reported in the literature in individuals affected with LDLR-related conditions. ClinVar contains an entry for this variant (Variation ID: 369873). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 23, 2023	Variant summary: LDLR c.467delA (p.Asn156ThrfsX50) 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. The variant was absent in 251262 control chromosomes (gnomAD). To our knowledge, no occurrence of c.467delA in individuals affected with Familial Hypercholesterolemia and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 20, 2018

Although the c.467delA likely pathogenic variant in the LDLR gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon asparagine 156, changing it to a threonine, and creating a premature stop codon at position 50 of the new reading frame, denoted p.Asn156ThrfsX50. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variants in the LDLR gene have been reported in Human Gene Mutation Database in association with FH (Stenson et al., 2014), and loss of function is a mechanism of disease for this gene. Furthermore, the c.467delA variant has not been observed in large population cohorts (Lek et al., 2016). -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2022

The c.467delA pathogenic mutation, located in coding exon 4 of the LDLR gene, results from a deletion of one nucleotide at nucleotide position 467, causing a translational frameshift with a predicted alternate stop codon (p.N156Tfs*50). This alteration has been reported in a genetic testing cohort of reportedly healthy individuals; however, clinical details were limited (Zouk et al. Am J Hum Genet, 2019 09;105:588-605). This alteration has also been reported in a subject that meets criteria for familial hypercholesterolemia (FH) (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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)		0.050		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: rs1057516135; hg19: chr19-11216047;