chr19-11107402-C-A

Variant names:

• chr19-11107402-C-A
• rs146651743
• NM_000527.5:c.828C>A

Variant summary

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

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:10 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 rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.828C>A	p.Cys276*	stop_gained	Exon 6 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.828C>A	p.Cys276*	stop_gained	Exon 6 of 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:10 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:7 Benign:1

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Institute for Integrative and Experimental Genomics, University of Luebeck

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PVS1+PS4+PP4 -

Nov 05, 2016

Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 20, 2023

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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. -

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Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 30, 2023

Mendelics

Significance: 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

- -

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Familial hypercholesterolemia Pathogenic:2

Sep 18, 2024

GENinCode PLC

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Aug 16, 2024

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); Also known as p.(C255X); This variant is associated with the following publications: (PMID: 25525159, 9399845, 10790219, 32977124, 21310417, 20538126, 33994402, 34456049, 26036859, 35379577, 17347910) -

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;