19-11105567-G-T

Variant names:

• chr19-11105567-G-T
• rs875989906
• NM_000527.5:c.661G>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS4_Moderate PS3 PP1_Strong PM1 PM2 PP3 PP4

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.661G>T (p.Asp221Tyr) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_Strong, PS3, PM1, PM2, PS4_Moderate, 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:PP1_Strong - Variant segregates with phenotype in 7 informative meiosis in at least 4 families from different labs (Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière)): 6 affected family members have the variant and 1 non-affected family members do not have the variant.PS3 - PMID:34167030 - Level 1 assay - Heterologous cells (CHO), FACS: Normal cell surface LDLR, 5% LDL-LDLR binding and 8% uptake.PM1 - Missense at codon 221. PM2 is Met and it is exon 4.PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PS4_moderate - Variant meets PM2. Variant identified in 9 unrelated index cases (1 case with Simon-Broome published in PMID 32331935; 2 cases with Simon Broome criteria from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; 6 cases with DLCN/Simon Broome criteria from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière).PP3 - REVEL = 0.978.PP4 - Variant meets PM2. Variant identified in 9 unrelated index cases (1 case with Simon-Broome published in PMID 32331935; 2 cases with Simon Broome criteria from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; 6 cases with DLCN/Simon Broome criteria from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585046/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 9.88
• Publications: 14 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: Pathogenic. The variant received 16 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• 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.
• 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 rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.661G>T	p.Asp221Tyr	missense_variant	Exon 4 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.661G>T	p.Asp221Tyr	missense_variant	Exon 4 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:5

Jun 01, 2022

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

NM_000527.5(LDLR):c.661G>T (p.Asp221Tyr) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_Strong, PS3, PM1, PM2, PS4_Moderate, 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: PP1_Strong - Variant segregates with phenotype in 7 informative meiosis in at least 4 families from different labs (Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière)): 6 affected family members have the variant and 1 non-affected family members do not have the variant. PS3 - PMID: 34167030 - Level 1 assay - Heterologous cells (CHO), FACS: Normal cell surface LDLR, 5% LDL-LDLR binding and 8% uptake. PM1 - Missense at codon 221. PM2 is Met and it is exon 4. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). PS4_moderate - Variant meets PM2. Variant identified in 9 unrelated index cases (1 case with Simon-Broome published in PMID 32331935; 2 cases with Simon Broome criteria from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; 6 cases with DLCN/Simon Broome criteria from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière). PP3 - REVEL = 0.978. PP4 - Variant meets PM2. Variant identified in 9 unrelated index cases (1 case with Simon-Broome published in PMID 32331935; 2 cases with Simon Broome criteria from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; 6 cases with DLCN/Simon Broome criteria from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière). -

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

0/190 non-FH alleles; 0/50 normolipidemic individuals -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only;research

- -

Aug 23, 2017

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial hypercholesterolemia Pathogenic:1

Mar 07, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp221 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15523646,23375686, 11196104, 15241806, 220236128, 2698793, 25461735). This suggests that this residue is clinically-significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed to segregate with familial hypercholesterolemia in a family (PMID: 9237502) and has been observed in individuals affected with this condition (PMID: 7649546, 7573037, 23375686, 10206683, 17765246, Invitae). This variant is also known as D200Y in the literature.  ClinVar contains an entry for this variant (Variation ID: 251356). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with tyrosine at codon 221 of the LDLR protein (p.Asp221Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.8	H;.;.;H
PhyloP100		9.9
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-8.3	D;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.95
MutPred		0.93		Loss of disorder (P = 0.025);Loss of disorder (P = 0.025);.;Loss of disorder (P = 0.025);
MVP		1.0
MPC		0.90
ClinPred		1.0	D
GERP RS		5.6
PromoterAI		-0.035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs875989906; hg19: chr19-11216243;