rs377271627

Variant names:

• chr19-11102769-C-G
• rs377271627
• NM_000527.5:c.296C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-11102769-C-G
• chr19-11102769-C-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS4 PS3_Supporting PVS1 PM2 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.296C>G (p.Ser99Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PS4, PM2, PP4 and PS3_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755).The supporting evidence is as follows: PVS1 - Variant is nonsense, causing a stop at codon 99. It is upstream of amino acid 830, so PVS1 is Met.PS4 - Variant meets PM2. Identified in over 20 unrelated clinical FH cases (PMID:7718019).PM2 - PopMax MAF = 0.000008791 (0.0009%) in european non-finnish exomes (gnomAD v2.1.1). PP4 - Variant meets PM2. Identified in over 20 unrelated clinical FH cases (PMID:7718019). PS3_supporting - Level 3 assays: PMID 19148831: Epstein-Barr virus transformed lymphocytes from htz patients, FACS and RNA assays - results - ~60% gene expression, LDL-LDLR uptake and protein at cell surface ---- results are below 85% of wild-type, so PS3_supporting is Met LINK:https://erepo.genome.network/evrepo/ui/classification/CA023685/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 3.38
• Publications: 6 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 16 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.296C>G	p.Ser99*	stop_gained	Exon 3 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.296C>G	p.Ser99*	stop_gained	Exon 3 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251478 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461450 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727032

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111736

Other (OTH) AF: 0.00 AC: 0 AN: 60360

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4

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

- -

Jun 07, 2021

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000527.5(LDLR):c.296C>G (p.Ser99Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PS4, PM2, PP4 and PS3_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PVS1 - Variant is nonsense, causing a stop at codon 99. It is upstream of amino acid 830, so PVS1 is Met. PS4 - Variant meets PM2. Identified in over 20 unrelated clinical FH cases (PMID: 7718019). PM2 - PopMax MAF = 0.000008791 (0.0009%) in european non-finnish exomes (gnomAD v2.1.1). PP4 - Variant meets PM2. Identified in over 20 unrelated clinical FH cases (PMID: 7718019). PS3_supporting - Level 3 assays: PMID 19148831: Epstein-Barr virus transformed lymphocytes from htz patients, FACS and RNA assays - results - ~60% gene expression, LDL-LDLR uptake and protein at cell surface ---- results are below 85% of wild-type, so PS3_supporting is Met -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

-

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Pathogenic:2

Jun 19, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP4, PM2, PS4, PVS1 -

Jan 06, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense 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: 24055113, 25637381, 25487149, 25525159, 34037665, 33955087, 7718019, 33740630) -

Familial hypercholesterolemia Pathogenic:2

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser99*) 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 present in population databases (rs377271627, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 7718019, 9259195, 9698020, 11857755, 23375686). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. This variant is also known as p.Ser78* and FH-Svartor. ClinVar contains an entry for this variant (Variation ID: 161269). For these reasons, this variant has been classified as Pathogenic. -

Aug 26, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pathogenic variant based on current evidence: This variant changes a single nucleotide in exon 3 of the LDLR gene, creating a 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. This variant has been reported in over 20 Norwegian individuals affected with familial hypercholesterolemia and is considered a founder mutation in that population (PMID: 7718019). This variant has also been reported in affected individuals in UK, Sweden, Netherlands and New Zealand (PMID: 9259195, 9698020, 11857755, 28964736). This variant is rare in the general population and has been identified in 1/246256 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic. -

Hypercholesterolemia Pathogenic:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Cardiovascular phenotype Pathogenic:1

Mar 27, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S99* pathogenic mutation (also known as c.296C>G), located in coding exon 3 of the LDLR gene, results from a C to G substitution at nucleotide position 296. This changes the amino acid from a serine to a stop codon within coding exon 3. This variant (historically referred to as FH-Svartor and p.S78X) is considered a Norwegian founder mutation, has been identified in many classic familial hypercholesterolemia (FH) patients, and has been reported to co-segregate with disease in several families (Leren TP et al. Atherosclerosis, 1994 Dec;111:175-82; Day IN et al. Hum. Mutat., 1997;10:116-27; Lind S et al. J. Intern. Med., 1998 Jul;244:19-25; Bunn CF et al. Hum. Mutat., 2002 Mar;19:311). 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

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	34
DANN	Uncertain	0.98
Eigen	Uncertain	0.30
Eigen_PC	Benign	-0.00092
FATHMM_MKL	Uncertain	0.86	D
PhyloP100		3.4
Vest4		0.89
GERP RS		4.6
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.0
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs377271627; hg19: chr19-11213445;