chr19-11113285-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP7BS1BP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR): c.1194C>T (p.Ile398=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BS1, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 22 July 2022. The supporting evidence is as follows:BS1 - FAF = 0.00448 (0.448%) in East Asian exomes (gnomAD v2.1.1).BP4 - No REVEL, splicing evaluation required.Functional data on splicing not available.Variant is not located within the limits of canonical splicing sitesVariant is exonic and at least 50bp upstream from canonical donor site but does not creates AGThere is no AG NearbyVariant is not predicted to alter splicing.BP7 - Variant is synonymous and meets BP4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA033001/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 29)

Exomes 𝑓: 0.0012 ( 17 hom. )

Consequence

LDLR
NM_000527.5 synonymous

Scores

Clinical Significance

Likely benign reviewed by expert panel P:1B:16

Conservation

PhyloP100: -1.08

Publications

7 publications found

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:

MIR6886 (HGNC:50121): (microRNA 6886) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR6886 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BP7

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.1194C>T	p.Ile398Ile	synonymous_variant	Exon 9 of 18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.1194C>T	p.Ile398Ile	synonymous_variant	Exon 9 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.00155

AC:

235

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.0106

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.0124

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00174

AC:

437

AN:

250716

AF XY:

0.00167

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00533

Gnomad FIN exome

AF:

0.0116

Gnomad NFE exome

AF:

0.000460

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00119

AC:

1745

AN:

1460576

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

849

AN XY:

726594

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33454

American (AMR)

AF:

0.000157

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26136

East Asian (EAS)

AF:

0.0174

AC:

690

AN:

39700

South Asian (SAS)

AF:

0.000615

AC:

AN:

86200

European-Finnish (FIN)

AF:

0.0108

AC:

571

AN:

53028

Middle Eastern (MID)

AF:

0.000394

AC:

AN:

5074

European-Non Finnish (NFE)

AF:

0.000326

AC:

362

AN:

1111960

Other (OTH)

AF:

0.000945

AC:

AN:

60304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

100

199

299

398

498

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00155

AC:

236

AN:

152198

Hom.:

Cov.:

AF XY:

0.00206

AC XY:

153

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41540

American (AMR)

AF:

0.000197

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3468

East Asian (EAS)

AF:

0.0108

AC:

AN:

5178

South Asian (SAS)

AF:

0.000830

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0124

AC:

132

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000529

AC:

AN:

68018

Other (OTH)

AF:

0.00142

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000496

Hom.:

Bravo

AF:

0.000623

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000356

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1Benign:16

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:1Benign:6

Jul 17, 2017

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 28, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, 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

- -

Mar 30, 2017

U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille

Significance:Likely pathogenic

Review Status:flagged submission

Collection Method:clinical testing

- -

Aug 31, 2016

Cardiovascular Biomarker Research Laboratory, Mayo Clinic

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

MAF =<0.3% -

May 18, 2021

Pars Genome Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 29, 2022

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000527.5(LDLR): c.1194C>T (p.Ile398=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying evidence code BS1, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: BS1 - FAF = 0.00448 (0.448%) in East Asian exomes (gnomAD v2.1.1). BP4 - No REVEL, splicing evaluation required. Functional data on splicing not available. Variant is not located within the limits of canonical splicing sites Variant is exonic and at least 50bp upstream from canonical donor site but does not creates AG There is no AG Nearby Variant is not predicted to alter splicing. BP7 - Variant is synonymous and meets BP4 -

not provided

Benign:4

Oct 10, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 09, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 17347910, 32719484) -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LDLR: BP4, BP7, BS1 -

not specified

Benign:2

Jun 19, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: LDLR c.1194C>T alters a non-conserved nucleotide resulting in a synonymous change. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0017 in 250716 control chromosomes, predominantly at a frequency of 0.0053 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013). c.1194C>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia (e.g. Al-Khateeb_2011, Komarova_2013) without evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. Co-occurrences with other pathogenic variant(s) have been reported (LDLR, p. Ser65Glyfs*64; LDLR, p. Trp562Cysfs*5), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21418584, 24373485). ClinVar contains an entry for this variant (Variation ID: 224620). Based on the evidence outlined above, the variant was classified as benign. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Familial hypercholesterolemia

Benign:2

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 17, 2024

GENinCode PLC

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BA1 -

Autosomal dominant familial hypercholesterolemia

Benign:1

May 30, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

May 13, 2016

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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

-0.51

CADD

Benign

6.4

(source)

DANN

Benign

0.76

PhyloP100

-1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=85/15

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over