chr19-11116124-C-T

Variant names:

• chr19-11116124-C-T
• rs5929
• NM_000527.5:c.1617C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: -3.35

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

Our verdict: Benign. The variant received -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
LDLR	NM_000527.5	c.1617C>T	p.Pro539Pro	synonymous_variant	Exon 11 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1617C>T	p.Pro539Pro	synonymous_variant	Exon 11 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes AF: 0.0726 AC: 11031 AN: 152010 Hom.: 614 Cov.: 32

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

GnomAD2 exomes AF: 0.0756 AC: 19015 AN: 251466 AF XY: 0.0735

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 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

Gnomad4 AFR exome AF: 0.116 AC: 3881 AN: 33408

Gnomad4 AMR exome AF: 0.0738 AC: 3298 AN: 44718

Gnomad4 ASJ exome AF: 0.0634 AC: 1657 AN: 26120

Gnomad4 EAS exome AF: 0.298 AC: 11820 AN: 39668

Gnomad4 SAS exome AF: 0.0801 AC: 6903 AN: 86202

Gnomad4 FIN exome AF: 0.0541 AC: 2890 AN: 53374

Gnomad4 NFE exome AF: 0.0392 AC: 43506 AN: 1110736

Gnomad4 Remaining exome AF: 0.0575 AC: 3467 AN: 60340

GnomAD4 genome AF: 0.0726 AC: 11048 AN: 152128 Hom.: 617 Cov.: 32 AF XY: 0.0746 AC XY: 5546 AN XY: 74372

Gnomad4 AFR AF: 0.110 AC: 0.110351 AN: 0.110351

Gnomad4 AMR AF: 0.0566 AC: 0.0566483 AN: 0.0566483

Gnomad4 ASJ AF: 0.0637 AC: 0.0637255 AN: 0.0637255

Gnomad4 EAS AF: 0.283 AC: 0.283165 AN: 0.283165

Gnomad4 SAS AF: 0.0853 AC: 0.0852697 AN: 0.0852697

Gnomad4 FIN AF: 0.0524 AC: 0.0524232 AN: 0.0524232

Gnomad4 NFE AF: 0.0404 AC: 0.0404106 AN: 0.0404106

Gnomad4 OTH AF: 0.0771 AC: 0.077105 AN: 0.077105

Alfa AF: 0.0573 Hom.: 330

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:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:8

-

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

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

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 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 -

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. -

Jun 22, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:4

Oct 21, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2022

GENinCode PLC

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

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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
Mutation Taster		=98/2	polymorphism (auto)

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