chr19-11116124-C-T

Variant summary

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

The NM_000527.5(LDLR):​c.1617C>T​(p.Pro539Pro) 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
NM_000527.5 synonymous

Scores

2

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]

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 rank MANE Protein UniProt
LDLRNM_000527.5 linkc.1617C>T p.Pro539Pro synonymous_variant Exon 11 of 18 ENST00000558518.6 NP_000518.1 P01130-1A0A024R7D5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LDLRENST00000558518.6 linkc.1617C>T p.Pro539Pro synonymous_variant Exon 11 of 18 1 NM_000527.5 ENSP00000454071.1 P01130-1

Frequencies

GnomAD3 genomes
AF:
0.0726
AC:
11031
AN:
152010
Hom.:
614
Cov.:
32
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.:
30
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.:
32
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
Jul 30, 2018
Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Due to the increased occurrence of the mutation (>= 5%), this variant is classified as benign. -

Mar 25, 2016
LDLR-LOVD, British Heart Foundation
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: literature only

- -

Jun 22, 2017
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 10, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Mar 01, 2016
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: research

8/95 non-FH individuals; MAF = 4,7% in 86 Spanish healthy individuals -

-
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: research

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not specified Benign:3
Oct 21, 2016
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Familial hypercholesterolemia Benign:3
Jul 15, 2022
GENinCode PLC
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 09, 2023
Cohesion Phenomics
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Apr 06, 2016
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Smith-Lemli-Opitz syndrome Benign:1
Sep 16, 2020
Natera, Inc.
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1
Dec 16, 2015
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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.

Other links and lift over

dbSNP: rs5929; hg19: chr19-11226800; COSMIC: COSV52943556; COSMIC: COSV52943556; API