19-11120205-T-C

Variant names:

• chr19-11120205-T-C
• rs5925
• NM_000527.5:c.1959T>C

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.1959T>C​(p.Val653Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.431 in 1,613,320 control chromosomes in the GnomAD database, including 154,103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11896 hom., cov: 32)
  • Exomes 𝑓: 0.44 (142207 hom.)
• Consequence: LDLR NM_000527.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: -0.228
• Publications: 104 publications found

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 Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 19-11120205-T-C is Benign according to our data. Variant chr19-11120205-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 252131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.228 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.497 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.1959T>C	p.Val653Val	synonymous	Exon 13 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.1959T>C	p.Val653Val	synonymous	Exon 13 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.1836T>C	p.Val612Val	synonymous	Exon 12 of 17	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.1959T>C	p.Val653Val	synonymous	Exon 13 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.2217T>C	p.Val739Val	synonymous	Exon 13 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.1959T>C	p.Val653Val	synonymous	Exon 13 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes AF: 0.377 AC: 57193 AN: 151854 Hom.: 11898 Cov.: 32

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.347

Gnomad AMR AF: 0.507

Gnomad ASJ AF: 0.420

Gnomad EAS AF: 0.216

Gnomad SAS AF: 0.436

Gnomad FIN AF: 0.497

Gnomad MID AF: 0.437

Gnomad NFE AF: 0.440

Gnomad OTH AF: 0.395

GnomAD2 exomes AF: 0.421 AC: 105927 AN: 251320 AF XY: 0.424

Gnomad AFR exome AF: 0.195

Gnomad AMR exome AF: 0.529

Gnomad ASJ exome AF: 0.433

Gnomad EAS exome AF: 0.222

Gnomad FIN exome AF: 0.487

Gnomad NFE exome AF: 0.436

Gnomad OTH exome AF: 0.426

GnomAD4 exome AF: 0.436 AC: 637807 AN: 1461348 Hom.: 142207 Cov.: 48 AF XY: 0.436 AC XY: 317056 AN XY: 727030

African (AFR) AF: 0.190 AC: 6357 AN: 33474

American (AMR) AF: 0.526 AC: 23540 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.436 AC: 11380 AN: 26128

East Asian (EAS) AF: 0.194 AC: 7697 AN: 39700

South Asian (SAS) AF: 0.434 AC: 37404 AN: 86252

European-Finnish (FIN) AF: 0.476 AC: 25416 AN: 53412

Middle Eastern (MID) AF: 0.456 AC: 2633 AN: 5768

European-Non Finnish (NFE) AF: 0.448 AC: 497842 AN: 1111522

Other (OTH) AF: 0.423 AC: 25538 AN: 60376

GnomAD4 genome AF: 0.376 AC: 57217 AN: 151972 Hom.: 11896 Cov.: 32 AF XY: 0.381 AC XY: 28269 AN XY: 74266

African (AFR) AF: 0.204 AC: 8444 AN: 41474

American (AMR) AF: 0.507 AC: 7720 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.420 AC: 1458 AN: 3470

East Asian (EAS) AF: 0.216 AC: 1116 AN: 5160

South Asian (SAS) AF: 0.435 AC: 2097 AN: 4820

European-Finnish (FIN) AF: 0.497 AC: 5251 AN: 10558

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.440 AC: 29861 AN: 67936

Other (OTH) AF: 0.392 AC: 828 AN: 2110

Alfa AF: 0.408 Hom.: 28103

Bravo AF: 0.368

Asia WGS AF: 0.338 AC: 1175 AN: 3478

EpiCase AF: 0.440

EpiControl AF: 0.444

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:7

Jun 22, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: literature only

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

MAF = 48,3% in 86 Spanish healthy individuals

Mar 06, 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.

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

Jul 16, 2018

Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Due to the increased occurrence of the mutation (>= 5%) and the current estimates of databases (LOVD 3), this variant is classified as likely benign.

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:6

Sep 30, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

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

Feb 07, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Val653Val in exon 13 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 53% (18213/34392) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.br oadinstitute.org; dbSNP rs5925). ACMG/AMP Criteria applied: BA1 (Richards 2015).

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Familial hypercholesterolemia Benign:4

Feb 09, 2023

Cohesion Phenomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 14, 2022

GENinCode PLC

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Nov 30, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Cardiovascular phenotype Benign:1

Dec 08, 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	5.8
DANN	Benign	0.66
PhyloP100		-0.23
Mutation Taster		=97/3	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

Other links and lift over

dbSNP: rs5925; hg19: chr19-11230881; COSMIC: COSV52943342;