rs5929

Positions:

chr19-11116124-C-T

Variant summary

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

The ENST00000558518.6(LDLR):c.1617C>T(p.Pro539=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0551 in 1,612,458 control chromosomes in the GnomAD database, including 4,226 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.073 ( 617 hom., cov: 32)

Exomes 𝑓: 0.053 ( 3609 hom. )

Consequence

LDLR
ENST00000558518.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.35

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=-0.72).

BP6

Variant 19-11116124-C-T is Benign according to our data. Variant chr19-11116124-C-T is described in ClinVar as [Benign]. Clinvar id is 251936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11116124-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-3.35 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.271 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.1617C>T	p.Pro539=	synonymous_variant	11/18	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.1617C>T	p.Pro539=	synonymous_variant	11/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0726

AC:

11031

AN:

152010

Hom.:

614

Cov.:

show subpopulations

Gnomad AFR

AF:

0.110

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0565

Gnomad ASJ

AF:

0.0637

Gnomad EAS

AF:

0.283

Gnomad SAS

AF:

0.0848

Gnomad FIN

AF:

0.0524

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.0404

Gnomad OTH

AF:

0.0755

GnomAD3 exomes

AF:

0.0756

AC:

19015

AN:

251466

Hom.:

1180

AF XY:

0.0735

AC XY:

9993

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.117

Gnomad AMR exome

AF:

0.0760

Gnomad ASJ exome

AF:

0.0667

Gnomad EAS exome

AF:

0.271

Gnomad SAS exome

AF:

0.0795

Gnomad FIN exome

AF:

0.0533

Gnomad NFE exome

AF:

0.0425

Gnomad OTH exome

AF:

0.0673

GnomAD4 exome

AF:

0.0532

AC:

77739

AN:

1460330

Hom.:

3609

Cov.:

AF XY:

0.0536

AC XY:

38940

AN XY:

726536

show subpopulations

Gnomad4 AFR exome

AF:

0.116

Gnomad4 AMR exome

AF:

0.0738

Gnomad4 ASJ exome

AF:

0.0634

Gnomad4 EAS exome

AF:

0.298

Gnomad4 SAS exome

AF:

0.0801

Gnomad4 FIN exome

AF:

0.0541

Gnomad4 NFE exome

AF:

0.0392

Gnomad4 OTH exome

AF:

0.0575

GnomAD4 genome

AF:

0.0726

AC:

11048

AN:

152128

Hom.:

617

Cov.:

AF XY:

0.0746

AC XY:

5546

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.110

Gnomad4 AMR

AF:

0.0566

Gnomad4 ASJ

AF:

0.0637

Gnomad4 EAS

AF:

0.283

Gnomad4 SAS

AF:

0.0853

Gnomad4 FIN

AF:

0.0524

Gnomad4 NFE

AF:

0.0404

Gnomad4 OTH

AF:

0.0771

Alfa

AF:

0.0559

Hom.:

212

Bravo

AF:

0.0757

Asia WGS

AF:

0.154

AC:

535

AN:

3478

EpiCase

AF:

0.0436

EpiControl

AF:

0.0404

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Benign:8

Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 22, 2017	- -
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 12, 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	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	Jul 30, 2018	Due to the increased occurrence of the mutation (>= 5%), this variant is classified as benign. -
Benign, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	8/95 non-FH individuals; MAF = 4,7% in 86 Spanish healthy individuals -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Familial hypercholesterolemia

Benign:3

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 15, 2022	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 06, 2016	Variant summary: This LDLR c.1617C>T variant affects a non-conserved nucleotide, resulting in synonymous amino acid change. 5/5 splice-site tools via Alamut predict that this variant does not affect normal splicing. This variant was found in 9229/121288 control chromosomes from the large and broad populations of ExAC at a frequency of 0.0760916 including several homozygotes, which is over 60 times greater than the maximal expected frequency of a pathogenic LDLR allele (0.0012508), suggesting this variant is benign. The variant has also been reported to co-occur with other potentially pathogenic variants such as c.68-1G>A (internal finding in one specimen), c.1634G>A (internal finding in one specimen), and p. p.Cys667Ser (Zakharova_2005), further supporting the benign outcome. Additionally, the variant is reported in the literature to be a common polymorphism that has no effect on plasma triglyceride, HDL cholesterol, apoA1 or lipoprotein (a) levels (Wu_Atheroscl_1999). Taken together, this variant has been classified as Benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Smith-Lemli-Opitz syndrome

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2015

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

-0.72

CADD

Benign

0.19

DANN

Benign

0.45

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

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