rs879254455

Positions:

• chr19-11102738-T-C
• chr19-11102738-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP3 PP1 PP4 PS4_Supporting PM1 PM3

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.265T>C (p.Cys89Arg) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM1, PM2, PM3, PS4_Supporting, PP1, PP3 and 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: PM1 - Variant meets PM2 and alters Cys89, one of the cysteine residues listed, so PM1 is Met.PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.PM3 - Variant meets PM2 and is identified in an index case with homozygous FH phenotype (LDL = 18.05 mmol/L) and LDLR variant c.1775G>A/p.(Gly592Glu), classified as Pathogenic by these guidelines, in trans, from ltaly (PMID:9974426), so PM3 is Met.PS4_Supporting - Variant meets PM2 and is identified in 5 unrelated index cases: 1 index case with possible FH (Simon-Broome criteria) from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, at least 1 index case with definite heterozygous FH from The Netherlands (PMID:16250003), 1 index case fulfilling MedPed criteria for FH from Spain (PMID:16627557), 2 index cases fulfilling WHO criteria for FH from Poland (PMID:20145306), so PS4_Supporting is Met.PP1 - Variant segregates with FH phenotype in 3 informative meiosis from 1 family from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge: 2 affected family members have the variant and 1 non-affected family member does not have the variant, so PP1 is Met.PP3 - REVEL = 0.973. It is above 0.75, so PP3 is Met.PP4 - Variant meets PM2 and is identified in 5 unrelated index cases fulfilling clinical criteria for FH from several labs (see PS4 for details), so PP4 is Met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10584817/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 7.97

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 10 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: 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.
• PP3: 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.265T>C	p.Cys89Arg	missense_variant	3/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.265T>C	p.Cys89Arg	missense_variant	3/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 14, 2022	- -
Likely pathogenic, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/208 non-FH alleles -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Mar 25, 2022	The NM_000527.5(LDLR):c.265T>C (p.Cys89Arg) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM1, PM2, PM3, PS4_Supporting, PP1, PP3 and 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: PM1 - Variant meets PM2 and alters Cys89, one of the cysteine residues listed, so PM1 is Met. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. PM3 - Variant meets PM2 and is identified in an index case with homozygous FH phenotype (LDL = 18.05 mmol/L) and LDLR variant c.1775G>A/p.(Gly592Glu), classified as Pathogenic by these guidelines, in trans, from ltaly (PMID: 9974426), so PM3 is Met. PS4_Supporting - Variant meets PM2 and is identified in 5 unrelated index cases: 1 index case with possible FH (Simon-Broome criteria) from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, at least 1 index case with definite heterozygous FH from The Netherlands (PMID: 16250003), 1 index case fulfilling MedPed criteria for FH from Spain (PMID: 16627557), 2 index cases fulfilling WHO criteria for FH from Poland (PMID: 20145306), so PS4_Supporting is Met. PP1 - Variant segregates with FH phenotype in 3 informative meiosis from 1 family from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge: 2 affected family members have the variant and 1 non-affected family member does not have the variant, so PP1 is Met. PP3 - REVEL = 0.973. It is above 0.75, so PP3 is Met. PP4 - Variant meets PM2 and is identified in 5 unrelated index cases fulfilling clinical criteria for FH from several labs (see PS4 for details), so PP4 is Met. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;.;.;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;T;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	1.0	D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.4	H;.;H;H;H
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-11	D;D;D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.97
MutPred		0.99		Gain of MoRF binding (P = 0.0276);Gain of MoRF binding (P = 0.0276);Gain of MoRF binding (P = 0.0276);Gain of MoRF binding (P = 0.0276);Gain of MoRF binding (P = 0.0276);
MVP		1.0
MPC		1.1
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.99
gMVP		1.0

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: rs879254455; hg19: chr19-11213414;