rs5930

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000527.5(LDLR):c.1413A>G(p.Arg471=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.621 in 1,613,574 control chromosomes in the GnomAD database, including 313,036 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.66 ( 33019 hom., cov: 31)

Exomes 𝑓: 0.62 ( 280017 hom. )

Consequence

LDLR
NM_000527.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: -0.476

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 Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 19-11113589-A-G is Benign according to our data. Variant chr19-11113589-A-G is described in ClinVar as [Benign]. Clinvar id is 200916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113589-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.476 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.1413A>G	p.Arg471=	synonymous_variant	10/18	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.1413A>G	p.Arg471=	synonymous_variant	10/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.655

AC:

99478

AN:

151868

Hom.:

32972

Cov.:

show subpopulations

Gnomad AFR

AF:

0.747

Gnomad AMI

AF:

0.530

Gnomad AMR

AF:

0.694

Gnomad ASJ

AF:

0.619

Gnomad EAS

AF:

0.610

Gnomad SAS

AF:

0.619

Gnomad FIN

AF:

0.647

Gnomad MID

AF:

0.630

Gnomad NFE

AF:

0.602

Gnomad OTH

AF:

0.626

GnomAD3 exomes

AF:

0.632

AC:

158684

AN:

251072

Hom.:

50512

AF XY:

0.626

AC XY:

85039

AN XY:

135748

show subpopulations

Gnomad AFR exome

AF:

0.747

Gnomad AMR exome

AF:

0.712

Gnomad ASJ exome

AF:

0.631

Gnomad EAS exome

AF:

0.609

Gnomad SAS exome

AF:

0.610

Gnomad FIN exome

AF:

0.639

Gnomad NFE exome

AF:

0.601

Gnomad OTH exome

AF:

0.612

GnomAD4 exome

AF:

0.618

AC:

902905

AN:

1461586

Hom.:

280017

Cov.:

AF XY:

0.616

AC XY:

448236

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.758

Gnomad4 AMR exome

AF:

0.710

Gnomad4 ASJ exome

AF:

0.629

Gnomad4 EAS exome

AF:

0.609

Gnomad4 SAS exome

AF:

0.613

Gnomad4 FIN exome

AF:

0.630

Gnomad4 NFE exome

AF:

0.610

Gnomad4 OTH exome

AF:

0.618

GnomAD4 genome

AF:

0.655

AC:

99574

AN:

151988

Hom.:

33019

Cov.:

AF XY:

0.656

AC XY:

48751

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.747

Gnomad4 AMR

AF:

0.694

Gnomad4 ASJ

AF:

0.619

Gnomad4 EAS

AF:

0.610

Gnomad4 SAS

AF:

0.619

Gnomad4 FIN

AF:

0.647

Gnomad4 NFE

AF:

0.602

Gnomad4 OTH

AF:

0.624

Alfa

AF:

0.613

Hom.:

67167

Bravo

AF:

0.663

Asia WGS

AF:

0.582

AC:

2027

AN:

3478

EpiCase

AF:

0.604

EpiControl

AF:

0.608

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Benign:7

Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	20 Hmz + 37 Htz / 92 non-FH individuals; MAF = 29,7% in 86 Spanish healthy individuals -
Benign, criteria provided, single submitter	clinical testing	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	May 23, 2018	Due to the increased occurrence of the mutation (>= 5%), this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 30, 2017	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 09, 2016	Arg471Arg in exon 10 of LDLR: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 38.4% (3301/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs5930). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Familial hypercholesterolemia

Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Feb 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GENinCode PLC	Jul 18, 2022	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2016

This alteration is classified as 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

BayesDel_noAF

Benign

-0.86

CADD

Benign

3.7

DANN

Benign

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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