chr19-11120502-A-T

Variant names:

• chr19-11120502-A-T
• rs879255143
• NM_000527.5:c.2120A>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PS4_Supporting PM2 PP3 PP4

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.2120A>T (p.Asp707Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.964. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 3 unrelated index cases who fulfill criteria for FH, after alternative causes of high cholesterol were excluded (2 cases with DLCN score >=6 from the Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; 1 case with DLCN score >=6 from Robarts Research Institute, Canada). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585780/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:7 U:1
• Conservation: PhyloP100: 7.27

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 Uncertain_significance. Variant got 5 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.2120A>T	p.Asp707Val	missense_variant	Exon 14 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2120A>T	p.Asp707Val	missense_variant	Exon 14 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:7 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4 Uncertain:1

Feb 23, 2024

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

NM_000527.5(LDLR):c.2120A>T (p.Asp707Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL = 0.964. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 3 unrelated index cases who fulfill criteria for FH, after alternative causes of high cholesterol were excluded (2 cases with DLCN score >=6 from the Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; 1 case with DLCN score >=6 from Robarts Research Institute, Canada). -

-

Robarts Research Institute, Western University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Dec 16, 2016

Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

subject mutated among 2600 FH index cases screened = 1 , family member = 1 with co-segregation/software prediction damaging -

Jul 21, 2023

deCODE genetics, Amgen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

The variant NM_000527.5:c.2120A>T (chr19:11120502) in LDLR was detected in 3 heterozygotes out of 58K WGS Icelanders (MAF= 0,003%). Following imputation in a set of 166K Icelanders (4 imputed heterozygotes) we observed an association with LDL cholesterol using measurements from 128289 individuals (Effect (SD)= 2.53, P= 8.17e-06), Non-HDL cholesterol using measurements from 136901 individuals (Effect (SD)= 2.31, P= 3.79e-05), pure hypercholesterolaemia using 1515 cases and 283197 controls (OR= 84.06, P= 3.36e-04) and myocardial infarction using 25692 cases and 320832 controls (OR= 56.16, P= 1.36e-03). This variant has been reported in ClinVar previously as likely pathogenic. Based on ACMG criteria (PS4, PM1, PP3, PP5_Strong) this variant classifies as likely pathogenic. -

not provided Pathogenic:1

Sep 08, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant that is likely pathogenic was identified in the LDLR gene. The D707V variant has been reported in association with FH (Marduel et al., 2010; Wang et al., 2016). The D707V variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D707V variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Finally, while missense variants in the same residue (D707N, D707Y) have been reported in the Human Gene Mutation Database in association with FH (Stenson et al., 2014), the pathogenicity of these variants has not been definitively determined. -

Cardiovascular phenotype Pathogenic:1

May 30, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D707V variant (also known as c.2120A>T), located in coding exon 14 of the LDLR gene, results from an A to T substitution at nucleotide position 2120. The aspartic acid at codon 707 is replaced by valine, an amino acid with highly dissimilar properties. This variant has been reported in individuals with familial hypercholesterolemia (FH) (Marduel M et al. Hum Mutat, 2010 Nov;31:E1811-24; Wang J et al. Arterioscler Thromb Vasc Biol, 2016 Dec;36:2439-2445; Björnsson E et al. Arterioscler Thromb Vasc Biol, 2021 Oct;41:2616-2628). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Familial hypercholesterolemia Pathogenic:1

Oct 30, 2019

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2120A>T (p.Asp707Val) variant in the LDLR gene has been reported in individuals with familial hypercholesterolemia (FH) (PMID: 20809525, 27765764) and is absent from general population databases. Multiple lines of in silico algorithms have predicted this p.Asp707Val change to be deleterious. In addition, missense variants in the same amino acid residue (p.Asp707Asn and p.Asp707Tyr) have also been reported in affected individuals with FH (PMID: 22881376, 19318025). Therefore, this c.2120A>T (p.Asp707Val) variant in the LDLR gene is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D;.;.;.;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.3	H;.;.;.;H
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-7.6	D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.97	D;.;.;.;.
Vest4		0.89
MutPred		0.76		Loss of disorder (P = 0.0447);Loss of disorder (P = 0.0447);.;.;Loss of disorder (P = 0.0447);
MVP		1.0
MPC		0.95
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.97
gMVP		0.97

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: rs879255143; hg19: chr19-11231178;