rs1799898

chr19-11116878-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000527.5(LDLR):c.1725C>T(p.Leu575=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 1,613,742 control chromosomes in the GnomAD database, including 13,006 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (994 hom., cov: 32)
  • Exomes 𝑓: 0.12 (12012 hom.)
• Consequence: LDLR NM_000527.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.878

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

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 19-11116878-C-T is Benign according to our data. Variant chr19-11116878-C-T is described in ClinVar as [Benign]. Clinvar id is 251997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11116878-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.878 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.1725C>T	p.Leu575=	synonymous_variant	12/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.1725C>T	p.Leu575=	synonymous_variant	12/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16752 AN: 152056 Hom.: 991 Cov.: 32

Gnomad AFR AF: 0.0821

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.0866

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.00752

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.126

GnomAD3 exomes AF: 0.112 AC: 28272 AN: 251468 Hom.: 1799 AF XY: 0.117 AC XY: 15840 AN XY: 135910

Gnomad AFR exome AF: 0.0821

Gnomad AMR exome AF: 0.0702

Gnomad ASJ exome AF: 0.135

Gnomad EAS exome AF: 0.00680

Gnomad SAS exome AF: 0.133

Gnomad FIN exome AF: 0.124

Gnomad NFE exome AF: 0.136

Gnomad OTH exome AF: 0.130

GnomAD4 exome AF: 0.124 AC: 181747 AN: 1461568 Hom.: 12012 Cov.: 37 AF XY: 0.125 AC XY: 91118 AN XY: 727090

Gnomad4 AFR exome AF: 0.0811

Gnomad4 AMR exome AF: 0.0715

Gnomad4 ASJ exome AF: 0.140

Gnomad4 EAS exome AF: 0.00662

Gnomad4 SAS exome AF: 0.132

Gnomad4 FIN exome AF: 0.130

Gnomad4 NFE exome AF: 0.131

Gnomad4 OTH exome AF: 0.122

GnomAD4 genome AF: 0.110 AC: 16766 AN: 152174 Hom.: 994 Cov.: 32 AF XY: 0.110 AC XY: 8200 AN XY: 74384

Gnomad4 AFR AF: 0.0820

Gnomad4 AMR AF: 0.0864

Gnomad4 ASJ AF: 0.151

Gnomad4 EAS AF: 0.00773

Gnomad4 SAS AF: 0.127

Gnomad4 FIN AF: 0.122

Gnomad4 NFE AF: 0.132

Gnomad4 OTH AF: 0.129

Alfa AF: 0.127 Hom.: 1096

Bravo AF: 0.105

Asia WGS AF: 0.0910 AC: 317 AN: 3478

EpiCase AF: 0.140

EpiControl AF: 0.140

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:7

Benign, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	4 Hmz + 27 Htz / 125 non-FH individuals; MAF = 11,0% in 86 Spanish healthy individuals -
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	clinical testing	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	Jun 11, 2018	Due to the increased occurrence of the mutation (>= 5%), this variant is classified as benign. -
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	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 15, 2017	Leu575Leu in exon 12 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 13.8% (1072/8600) of European chromosomes from a broad population by the Exome Aggregation Consortiu m (ExAC, http://exac.broadinstitute.org; dbSNP rs1799898). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2016	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Familial hypercholesterolemia Benign:3

Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Feb 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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

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	-0.55
Cadd	Benign	4.1
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1799898; hg19: chr19-11227554; COSMIC: COSV52943496; COSMIC: COSV52943496;