rs377437226

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP4PS4_SupportingPVS1_Moderate

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:11

Conservation

PhyloP100: 3.80

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.2546C>A	p.Ser849Ter	stop_gained, splice_region_variant	17/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.2546C>A	p.Ser849Ter	stop_gained, splice_region_variant	17/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

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:

AN:

1461710

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727162

show subpopulations

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 27, 2022	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2021	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. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 22, 2021	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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 14, 2022	- -

Familial hypercholesterolemia

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Oct 12, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 09, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 08, 2020	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. -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 13, 2020	- -

LDLR-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 26, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.90

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

Vest4

0.71

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over