rs688

Positions:

chr19-11116926-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.1773C>T(p.Asn591=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.417 in 1,613,584 control chromosomes in the GnomAD database, including 147,093 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.34 ( 10427 hom., cov: 31)

Exomes 𝑓: 0.43 ( 136666 hom. )

Consequence

LDLR
NM_000527.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21

Conservation

PhyloP100: -4.22

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=-0.74).

BP6

Variant 19-11116926-C-T is Benign according to our data. Variant chr19-11116926-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 200917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11116926-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-4.22 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.433 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.1773C>T	p.Asn591=	synonymous_variant	12/18	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.1773C>T	p.Asn591=	synonymous_variant	12/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.337

AC:

51230

AN:

151818

Hom.:

10439

Cov.:

show subpopulations

Gnomad AFR

AF:

0.107

Gnomad AMI

AF:

0.349

Gnomad AMR

AF:

0.427

Gnomad ASJ

AF:

0.419

Gnomad EAS

AF:

0.173

Gnomad SAS

AF:

0.393

Gnomad FIN

AF:

0.493

Gnomad MID

AF:

0.434

Gnomad NFE

AF:

0.437

Gnomad OTH

AF:

0.362

GnomAD3 exomes

AF:

0.389

AC:

97866

AN:

251472

Hom.:

20537

AF XY:

0.396

AC XY:

53812

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.100

Gnomad AMR exome

AF:

0.415

Gnomad ASJ exome

AF:

0.432

Gnomad EAS exome

AF:

0.179

Gnomad SAS exome

AF:

0.389

Gnomad FIN exome

AF:

0.483

Gnomad NFE exome

AF:

0.434

Gnomad OTH exome

AF:

0.409

GnomAD4 exome

AF:

0.426

AC:

622001

AN:

1461646

Hom.:

136666

Cov.:

AF XY:

0.425

AC XY:

309181

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.0953

Gnomad4 AMR exome

AF:

0.419

Gnomad4 ASJ exome

AF:

0.435

Gnomad4 EAS exome

AF:

0.148

Gnomad4 SAS exome

AF:

0.393

Gnomad4 FIN exome

AF:

0.472

Gnomad4 NFE exome

AF:

0.447

Gnomad4 OTH exome

AF:

0.407

GnomAD4 genome

AF:

0.337

AC:

51210

AN:

151938

Hom.:

10427

Cov.:

AF XY:

0.341

AC XY:

25314

AN XY:

74240

show subpopulations

Gnomad4 AFR

AF:

0.107

Gnomad4 AMR

AF:

0.426

Gnomad4 ASJ

AF:

0.419

Gnomad4 EAS

AF:

0.172

Gnomad4 SAS

AF:

0.393

Gnomad4 FIN

AF:

0.493

Gnomad4 NFE

AF:

0.437

Gnomad4 OTH

AF:

0.360

Alfa

AF:

0.414

Hom.:

25163

Bravo

AF:

0.321

Asia WGS

AF:

0.266

AC:

923

AN:

3478

EpiCase

AF:

0.438

EpiControl

AF:

0.442

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:21

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Benign:9

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -
Likely 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%) and the current estimates of databases (LOVD 3), this variant is classified as likely benign. -
Benign, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	19 Hmz + 62 htz / 125 non-FH individuals; MAF = 48,3% in 86 Spanish healthy individuals -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 22, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	Population allele frequency is 38% (rs688, 106341/277102 alleles in gnomAD v2.0.2). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as Benign. Following criteria met: BA1. -
Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 25, 2022	- -
Benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 31, 2015	p.Asn591Asn in exon 12 of LDLR: This variant is not expected to have clinical si gnificance because it has been identified in 37.8% (45902/121396) of chromosomes tested by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs688). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Familial hypercholesterolemia

Benign:4

Benign, criteria provided, single submitter	clinical testing	GENinCode PLC	Jul 14, 2022	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Feb 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 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

-0.74

CADD

Benign

0.092

DANN

Benign

0.70

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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