rs148698650

chr19-11107403-G-Achr19-11107403-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1 PM2 BP4_Strong BP6

The NM_000527.5(LDLR):c.829G>A(p.Glu277Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000449 in 1,611,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E277D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:17 O:1
• Conservation: PhyloP100: 2.64

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 Likely_benign. Variant got -1 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 10 uncertain in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05303049).
• BP6: Variant 19-11107403-G-A is Benign according to our data. Variant chr19-11107403-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 183097.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Uncertain_significance=7, not_provided=1, Benign=4}. Variant chr19-11107403-G-A is described in Lovd as [Benign]. Variant chr19-11107403-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.829G>A	p.Glu277Lys	missense_variant	6/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.829G>A	p.Glu277Lys	missense_variant	6/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152062 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000537 AC: 135 AN: 251424 Hom.: 0 AF XY: 0.000625 AC XY: 85 AN XY: 135908

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00157

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000343

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000457 AC: 667 AN: 1459172 Hom.: 0 Cov.: 32 AF XY: 0.000496 AC XY: 360 AN XY: 725900

Gnomad4 AFR exome AF: 0.000210

Gnomad4 AMR exome AF: 0.00108

Gnomad4 ASJ exome AF: 0.000422

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00174

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000365

Gnomad4 OTH exome AF: 0.000598

GnomAD4 genome AF: 0.000375 AC: 57 AN: 152180 Hom.: 0 Cov.: 31 AF XY: 0.000457 AC XY: 34 AN XY: 74402

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000377 Hom.: 0

Bravo AF: 0.000453

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000502 AC: 61

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:17 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:5 Benign:6

Likely benign, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Jan 31, 2024	This missense variant LDLR c.829G>A (also known as p.Glu256Lys in the mature protein), replaces a glutamic acid with lysine at codon 277 of the LDLR protein (p.Glu277Lys). According to updated genomic data and to ClinGen FH VCEP criteria issued in 2022 (PMID: 34906454) for the validation of pathogenicity of LDLR variants, this variant may now be reclassified as “Likely Benign” from evidence as follows. It is located within a moderately conserved (REVEL=0.33) functional domain (LDLR Class A7) involved in LDL binding with LDL receptors (BP4). It is observed with a frequency exceeding 0.02% in the general population (GnomAD= 0.000375, no homozygotes) and despite apparent cosegregation in some families, it has been often reported in Cis with other proven pathogenic variants, and notably with the c.1268T>C (p.Ile423Thr) in populations of European ancestry (BP2). Finally, several independent level 1 in-vitro functional studies have shown consistently that this variant has a neutral effect on LDLR function (BS3). -
Likely benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Uncertain significance, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/190 non-FH alleles; 0/60 healthy control individuals -
Likely benign, criteria provided, single submitter	research	Cardiovascular Biomarker Research Laboratory, Mayo Clinic	Aug 31, 2015	MAF =<0.3%, likely pathogenic based on the integrative in-silico score. "Little/No effect" on the LDL receptor activity based on experimental validation. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Uncertain significance, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Mar 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	subjects mutated among 2600 FH index cases screened = 15 , family members = 5 / for 14 index cases among 15 this variant is associated with c.1268T>C, p.Ile423Thr that seems to be more deleterious / Software predictions: Conflicting -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 12, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 29, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 01, 2021	Variant summary: LDLR c.829G>A (p.Glu277Lys) results in a conservative amino acid change located in a class A repeat (IPR002172) in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00054 in 251484 control chromosomes, predominantly within the South Asian and Southern European subpopulations at a frequency of 0.0016 and 0.0012, respectively (gnomAD). The observed variant frequency in these subpopulations is close to- or higher than the expected allele frequency for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013), strongly suggesting that the variant is a benign polymorphism. c.829G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia, but also in controls (e.g. Ekstrom_1995, Pereira_1995, Descamps_1997, Ekstrom_2000, Weiss_2000, Fouchier_2001, Bertolini_2000, Mozas_2004. Ejarque_2008). Of note, in many of these patients co-occurrences with other pathogenic variants in cis have been reported (e.g. c.12G>A (p.Trp4X), c.460C>T (p.Gln154X), c.1326C>G (p.Tyr442X), c.2393_2401del9; see e.g. in Mozas_2004), providing supporting evidence for a benign role. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated normal expression level, and LDL uptake for the variant protein (e.g. Ekstrom_2000, Thormaehlen_2015, RodriguezJimenez_2019). 13 other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as benign. -

Familial hypercholesterolemia Uncertain:1 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 03, 2020	- -
Uncertain significance, criteria provided, single submitter	research	Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 27, 2018	- -

not provided Benign:3 Other:1

not provided, no classification provided	in vitro	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 11, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 24, 2023	- -

LDLR-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 07, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D;.;.;.;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.025
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.053	T;T;T;T;T;T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	1.3	L;.;.;.;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-2.2	N;N;N;N;N;N
Sift	Benign	0.28	T;T;T;T;T;T
Sift4G	Benign	0.18	T;T;T;T;T;T
Polyphen		0.29	B;.;.;.;.;.
Vest4		0.42
MVP		1.0
MPC		0.37
ClinPred		0.022	T
GERP RS		5.3
Varity_R		0.41
gMVP		0.83

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: rs148698650; hg19: chr19-11218079; COSMIC: COSV52946021; COSMIC: COSV52946021;