rs730882103

chr19-11113686-A-Gchr19-11113686-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000527.5(LDLR):c.1510A>G(p.Lys504Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:2 O:1
• Conservation: PhyloP100: 2.02

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.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 11 uncertain in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.1510A>G	p.Lys504Glu	missense_variant	10/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.1510A>G	p.Lys504Glu	missense_variant	10/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251454 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461864 Hom.: 0 Cov.: 35 AF XY: 0.0000289 AC XY: 21 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74326

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:4 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 15, 2023	This missense variant (also known as p.Lys483Glu in the mature protein) replaces lysine with glutamic acid at codon 504 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A cell-based experimental study has shown that this variant does not disrupt LDL uptake function of the protein (PMID: 25647241). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 15199436, 25647241; Color internal data). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 27784735). Additionally, this variant has been reported in individuals affected with myocardial infarction (PMID: 25487149). This variant has been identified in 3/251454 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Uncertain significance, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Uncertain significance, 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.1510A>G (p.Lys504Glu), replaces lysine with glutamic acid at codon 504 of the LDLR protein. 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 classified as “Variant of Uncertain Significance” from conflicting evidence as follows. This variant is located within a conserved (REVEL=0.529) functional domain (LDLR Class B3) involved in LDL receptor recycling to the plasma membrane (PP3-supporting). This variant is observed with a frequency <0.02% (PM2), in the general population (GnomAD= 0.0000197, no homozygotes). It was observed in hypercholesterolemic individuals and reported to cosegregate with FH in independent families of European ancestry (PS4-supporting). However, level 1 in-vitro functional studies have shown that this variant has a neutral effect on LDLR function (BS3). -
Uncertain significance, 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	subject mutated among 2600 FH index cases screened = 1/Software predictions: Benign -

Familial hypercholesterolemia Uncertain:3

Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Lys504Glu variant in LDLR has been reported in 1 Italian and 2 Norwegian individuals with familial hypercholesterolemia (PMID: 25647241, PMID: 15199436), but has been identified in 0.003% (3/113736) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs730882103). This variant has also been reported in ClinVar as having conflicint interpretations of pathogenicity (Variation ID: rs730882103). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_supporting (Richards 2015). -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 30, 2021	This sequence change replaces lysine with glutamic acid at codon 504 of the LDLR protein (p.Lys504Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs730882103, ExAC 0.008%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 15199436, 19318025, 25487149). ClinVar contains an entry for this variant (Variation ID: 183117). 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 tolerated. Experimental studies have shown that this missense change does not substantially affect LDLR function (PMID: 25647241). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 03, 2023	This missense variant (also known as p.Lys483Glu in the mature protein) replaces lysine with glutamic acid at codon 504 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A cell-based experimental study has shown that this variant does not disrupt LDL uptake function of the protein (PMID: 25647241). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 15199436, 25647241; Color internal data). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 27784735). Additionally, this variant has been reported in individuals affected with myocardial infarction (PMID: 25487149). This variant has been identified in 3/251454 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 13, 2024

Variant summary: LDLR c.1510A>G (p.Lys504Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251454 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1510A>G has been reported in the literature in individuals affected with Familial Hypercholesterolemia. These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant. ClinVar contains an entry for this variant (Variation ID: 183117). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Other:1

not provided, no classification provided

in vitro

Dept. of Genetics and Pharmacogenomics, Merck Research Labs

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	0.090
Cadd	Benign	14
Dann	Benign	0.90
DEOGEN2	Uncertain	0.48	T;.;.;.;.;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.76
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.85	T;T;T;T;T;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	-0.67	N;.;.;.;.;N
MutationTaster	Benign	0.94	D;D;N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.66	N;N;N;N;N;N
Sift	Benign	0.21	T;T;T;T;T;T
Sift4G	Benign	0.34	T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;.;.
Vest4		0.35
MutPred		0.83		Loss of MoRF binding (P = 0.0075);Loss of MoRF binding (P = 0.0075);.;.;.;Loss of MoRF binding (P = 0.0075);
MVP		1.0
MPC		0.30
ClinPred		0.047	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.38
gMVP		0.89

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: rs730882103; hg19: chr19-11224362;