rs377437226

Variant names:

• chr19-11129669-C-A
• rs377437226
• NM_000527.5:c.2546C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11129669-C-A
• chr19-11129669-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP4 PS4_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.2546C>A (p.Ser849Ter) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PVS1_Moderate, PP4 and PS4_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: PM2 - No population data was found for this allele in gnomAD (gnomAD v2.1.1).PVS1_moderate - Variant is nonsense after amino acid 830 (NM_000527.5:p.Lys830).PP4 - Variant meets PM2. Variant identified in 2 index FH cases (1 case from Color laboratory with Simon-Broome criteria; 1 case with Simon-Broome criteria published in PMID:26892515).PS4_supporting - Variant meets PM2. Variant identified in 2 index cases (1 case from Color laboratory with Simon-Broome criteria; 1 case with Simon-Broome criteria published in PMID:26892515). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585878/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: LDLR NM_000527.5 stop_gained, splice_region
• Scores: Splicing: ADA: 0.8872
• Clinical Significance: Likely pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 3.80
• Publications: 4 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.2546C>A	p.Ser849*	stop_gained splice_region	Exon 17 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.2546C>A	p.Ser849*	stop_gained splice_region	Exon 17 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.2423C>A	p.Ser808*	stop_gained splice_region	Exon 16 of 17	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.2546C>A	p.Ser849*	stop_gained splice_region	Exon 17 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.2804C>A	p.Ser935*	stop_gained splice_region	Exon 17 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.2546C>A	p.Ser849*	stop_gained splice_region	Exon 17 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152136 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461710 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727162

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111944

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152136 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74334

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:12

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:6

Jul 27, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

Jun 22, 2021

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

NM_000527.5(LDLR):c.2546C>A (p.Ser849Ter) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PVS1_Moderate, PP4 and PS4_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: PM2 - No population data was found for this allele in gnomAD (gnomAD v2.1.1). PVS1_moderate - Variant is nonsense after amino acid 830 (NM_000527.5:p.Lys830). PP4 - Variant meets PM2. Variant identified in 2 index FH cases (1 case from Color laboratory with Simon-Broome criteria; 1 case with Simon-Broome criteria published in PMID: 26892515). PS4_supporting - Variant meets PM2. Variant identified in 2 index cases (1 case from Color laboratory with Simon-Broome criteria; 1 case with Simon-Broome criteria published in PMID: 26892515).

Mar 28, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser849X variant in LDLR has been reported in 1 individual with familial hypercholesterolemia (FH) (Sharifi 2016 PMID: 26892515). A variant with a different nucleotide change (c.2546delC) that resulted in the same protein change was also reported in one individual with FH (Salazar 2002 PMID: 11933210). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 252350) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 849. This alteration occurs within the terminal 50 bases of the last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein that is missing <2% of the coding region, with 13 amino acids removed. This variant is expected to disrupt a part of the C-terminal cytoplasmic domain, which is required for internalization of the LDLR protein (Hobbs 1990 PMID: 2088165, Dvir 2012 PMID: 22509010). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant FH. ACMG/AMP criteria applied: PVS1_Strong, PM2_Supporting, PS4_Supporting.

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Jun 14, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial hypercholesterolemia Pathogenic:4

Oct 12, 2018

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2546C>A (p.Ser849*) variant in the LDLR gene is predicted to introduce a premature translation termination codon. This variant has not been reported in general population databases. Therefore, this c.2546C>A (p.Ser849*) variant is classified as likely pathogenic.

Apr 08, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes the last 12 amino acids from C-terminal cytoplasmic domain of the LDLR protein. This variant may not result in nonsense mediated mRNA decay but is expected to disrupt a part of the C-terminal cytoplasmic domain, which is required for internalization of the LDLR protein (PMID: 22509010, 2088165). Although functional studies have not been reported, this variant is likely to have a deleterious impact on the LDLR function. This variant and a different variant with the same protein effect (c.2546del) have been observed in two individuals affected with familial hypercholesterolemia (PMID: 26892515, 11933210). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

Aug 13, 2020

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 15, 2024

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.Ser849*) in the LDLR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 12 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 individuals with familial hypercholesterolemia (PMID: 11933210, 26892515). ClinVar contains an entry for this variant (Variation ID: 252350). This variant disrupts a region of the LDLR protein in which other variant(s) (Deletion (Exon 18)) have been determined to be pathogenic (PMID: 16159606; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

LDLR-related disorder Pathogenic:1

Jun 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The LDLR c.2546C>A variant is predicted to result in premature protein termination (p.Ser849*). This variant was reported in an individual with hypercholesterolemia (Sharifi et al 2016. PubMed ID: 26892515). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been interpreted as likely pathogenic by the ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/252350/). Nonsense variants in LDLR are expected to be pathogenic. This variant is interpreted as likely pathogenic.

Cardiovascular phenotype Pathogenic:1

Apr 17, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S849* variant (also known as c.2546C>A), located in coding exon 17 of the LDLR gene, results from a C to A substitution at nucleotide position 2546. This changes the amino acid from a serine to a stop codon within coding exon 17. This variant was reported in individual(s) with features consistent with familial hypercholesterolemia (Sharifi M et al. Metabolism, 2016 Mar;65:48-53; Raslova K et al. J Clin Lipidol. 2024 Mar;18(4):e537-e547; external communication). This alteration occurs at the 3' terminus of theLDLR gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 1.3% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Banerjee K et al. Biochemistry. 2018 07;57(30):4395-4403; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.90	D
PhyloP100		3.8
Vest4		0.71
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.89
dbscSNV1_RF	Benign	0.72
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: rs377437226; hg19: chr19-11240345;