rs146651743

Positions:

• chr19-11107402-C-A
• chr19-11107402-C-G
• chr19-11107402-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PP1 PP4 PM3 PS4 PM2 PVS1

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.828C>A (p.Cys276Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PS4, PM2, PM3, PP1, PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:-PVS1: Variant is predicted to result in a stop codon at amino acid 276, which is amino-terminal of amino acid 830.-PS4: Variant meets PM2 and is identified in 12 unrelated index cases (3 cases with Simon-Broome criteria of possible FH and 6 cases with Simon-Broome criteria of definite FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), 1 case with DLCN>=6 from PMID:32977124, homozygous FH; 1 cases with SB possible FH from PMID:26036859, and 1 case with FH by MedPed criteria from PMID 21310417).-PM2: This variant is absent from gnomAD (gnomAD v2.1.1).-PM3: Variant identified as homozygous state in an index case with homozygous FH phenotype from PMID:32977124.-PP1: Variant segregates with FH phenotype in at least 2 informative meiosis from 2 families from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation).-PP4: Variant meets PM2 and is identified in 12 unrelated index cases (3 cases with Simon-Broome criteria of possible FH and 6 cases with Simon-Broome criteria of definite FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), 1 case with DLCN>=6 from PMID:32977124, homozygous FH; 1 cases with SB possible FH from PMID:26036859, and 1 case with FH by MedPed criteria from PMID 21310417), after alternative causes of high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023773/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:9 B:1
• Conservation: PhyloP100: -3.11

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: 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.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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	c.828C>A	p.Cys276*	stop_gained	6/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.828C>A	p.Cys276*	stop_gained	6/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:7 Benign:1

Likely benign, criteria provided, single submitter	research	Institute for Integrative and Experimental Genomics, University of Luebeck	-	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Mar 20, 2023	The NM_000527.5(LDLR):c.828C>A (p.Cys276Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PS4, PM2, PM3, PP1, PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: -PVS1: Variant is predicted to result in a stop codon at amino acid 276, which is amino-terminal of amino acid 830. -PS4: Variant meets PM2 and is identified in 12 unrelated index cases (3 cases with Simon-Broome criteria of possible FH and 6 cases with Simon-Broome criteria of definite FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), 1 case with DLCN>=6 from PMID: 32977124, homozygous FH; 1 cases with SB possible FH from PMID: 26036859, and 1 case with FH by MedPed criteria from PMID 21310417). -PM2: This variant is absent from gnomAD (gnomAD v2.1.1). -PM3: Variant identified as homozygous state in an index case with homozygous FH phenotype from PMID: 32977124. -PP1: Variant segregates with FH phenotype in at least 2 informative meiosis from 2 families from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation). -PP4: Variant meets PM2 and is identified in 12 unrelated index cases (3 cases with Simon-Broome criteria of possible FH and 6 cases with Simon-Broome criteria of definite FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), 1 case with DLCN>=6 from PMID: 32977124, homozygous FH; 1 cases with SB possible FH from PMID: 26036859, and 1 case with FH by MedPed criteria from PMID 21310417), after alternative causes of high cholesterol were excluded. -
Pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PVS1+PS4+PP4 -
Pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Mar 30, 2023	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Apr 25, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189298). This premature translational stop signal has been observed in individual(s) with autosomal dominant familial hypercholesterolemia (PMID: 10790219). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys276*) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	GENinCode PLC	Sep 18, 2024	The LDLR c.828C>A p.(Cys276Ter) variant is a nonsense variant predicted to result in a stop codon at amino acid 276, which is amino-terminal of amino acid 830 (PVS1_VERY STRONG). This variant has been identified in >=10 unrelated FH probands meeting clinical criteria, including patients where alternative causes of high cholesterol were excluded (PS4_STRONG, PP4_SUPPORTING; PMIDs 10790219, 20538126, 22698793, 26036859, ClinGen FH VCEP data). This variant was observed in the homozygous state in an individual with a homozygous FH phenotype (PM3_MODERATE; PMID: 32977124) and was found to segregate with FH in at least 2 informative meiosis from 2 families (PP1_SUPPORTING; ClinGen FH VCEP data). This variant is absent from gnomAD v2.1.1 (PM2_MODERATE). Based on the evidence listed above, we have classified this variant as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	18
DANN	Benign	0.95
Eigen	Benign	-0.58
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.39	N
Vest4		0.97
GERP RS		-8.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs146651743; hg19: chr19-11218078;