rs139507589

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.758G>A (p.Arg253Gln) variant is classified as Uncertain significance – insufficient evidence for Familial Hypercholesterolemia by applying evidence PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.000096 (0.0096%) in Ashkenazi Jewish exomes+genomes (gnomAD v2.1.1). BP4 - REVEL = 0.44; score is below 0.5 threshold, splicing evaluation required. Functional data on splicing not available. Category B) - variant is exonic and at least 50bp upstream from the canonical donor site, and creates an AG. MES scores: de novo variant = 0; canonical acceptor site = 10.79; ratio = 0/10.79 = 0; this is below the threshold of 0.8 and therefore this variant is predicted to not affect splicing. Note: two other missense variants at this same codon have been reported: 1) NM_000527.5(LDLR):c.757C>T (p.Arg253Trp); 2) NM_000527.5(LDLR):c.758G>C (p.Arg253Pro); however, both are VUS by these LDLR guidelines (PM5 not applicable). LINK:https://erepo.genome.network/evrepo/ui/classification/CA029258/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:7

Conservation

PhyloP100: 0.678

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

BP4

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 linkuse as main transcript	c.758G>A	p.Arg253Gln	missense_variant	5/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.758G>A	p.Arg253Gln	missense_variant	5/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251480

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 05, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 28, 2023	Variant of Uncertain Significance due to insufficient evidence: This missense variant (also known as p.Arg232Gln in the mature protein) is located in the LDLR type A repeat 6 of ligand binding domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 4/277252 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively. -
Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Apr 22, 2022	The NM_000527.5(LDLR):c.758G>A (p.Arg253Gln) variant is classified as Uncertain significance – insufficient evidence for Familial Hypercholesterolemia by applying evidence PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.000096 (0.0096%) in Ashkenazi Jewish exomes+genomes (gnomAD v2.1.1). BP4 - REVEL = 0.44; score is below 0.5 threshold, splicing evaluation required. Functional data on splicing not available. Category B) - variant is exonic and at least 50bp upstream from the canonical donor site, and creates an AG. MES scores: de novo variant = 0; canonical acceptor site = 10.79; ratio = 0/10.79 = 0; this is below the threshold of 0.8 and therefore this variant is predicted to not affect splicing. Note: two other missense variants at this same codon have been reported: 1) NM_000527.5(LDLR):c.757C>T (p.Arg253Trp); 2) NM_000527.5(LDLR):c.758G>C (p.Arg253Pro); however, both are VUS by these LDLR guidelines (PM5 not applicable). -

Familial hypercholesterolemia

Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 17, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 253 of the LDLR protein (p.Arg253Gln). This variant is present in population databases (rs139507589, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with LDLR-related conditions. ClinVar contains an entry for this variant (Variation ID: 843407). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	Feb 09, 2023	This missense variant (also known as p.Arg232Gln in the mature protein) replaces arginine with glutamine at codon 253 of the LDLR protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected to be affected with familial hypercholesterolemia (doi:10.3390/jcm12031030). This variant has been identified in 4/282886 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. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 24, 2023

The p.R253Q variant (also known as c.758G>A), located in coding exon 5 of the LDLR gene, results from a G to A substitution at nucleotide position 758. The arginine at codon 253 is replaced by glutamine, an amino acid with highly similar properties. This variant co-occurred with a pathogenic mutation in the LDLR gene in an individual from a familial hypercholesterolemia cohort (Aparicio A et al. J Clin Med, 2023 Jan;12). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.015

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

D;.;.;.;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.14

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D;D;D;D

M_CAP

Pathogenic

0.34

MetaRNN

Benign

0.36

T;T;T;T;T

MetaSVM

Uncertain

0.12

MutationAssessor

Benign

0.43

N;.;.;.;N

MutationTaster

Benign

0.99

D;D;D;D;D;D;D

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-2.5

N;N;N;N;N

REVEL

Uncertain

0.44

Sift

Benign

0.17

T;T;T;T;T

Sift4G

Benign

0.30

T;T;T;T;T

Polyphen

0.41

B;.;.;.;.

Vest4

0.37

MVP

1.0

MPC

0.29

ClinPred

0.37

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.16

gMVP

0.73

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over