19-11102706-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3PP4PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.233G>A (p.Arg78His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PS4_Supporting and PP4 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: PM2 - PopMax MAF = 0.0001202 (0.012%) in African/African American exomes+genomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met.PP3 - REVEL = 0.806. It is above 0.75, so PP3 is met.PS4_supporting - variant meets PM2 and was identified in:- 1 index case with SB criteria of FH from PMID 31993549 (Garg et al., 2019), North America;- 1 index case with DLCN at least 8 (TC>10mmol/L and xanthomas) from PMID 27830735 (Jiang et al. 2016), China;- 1 index case with MEDPED criteria of FH from Benyahya et al. (2010) (paper cited in HGMD), Morocco;3 unrelated index cases, so PS4_Supporting is met.PP4 - variant meets PM2 and was identified in 3 unrelated index cases who fulfill clinical criteria for FH after alternative causes of high cholesterol were excluded (please see PS4 for details), so PP4 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA042534/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:8B:1

Conservation

PhyloP100: 1.51

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 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

LDLR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PS4

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

PM2

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

PP3

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

PP4

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.233G>A	p.Arg78His	missense_variant	Exon 3 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.233G>A	p.Arg78His	missense_variant	Exon 3 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000557

AC:

AN:

251490

AF XY:

0.0000809

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000105

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000862

AC:

126

AN:

1461474

Hom.:

Cov.:

AF XY:

0.0000922

AC XY:

AN XY:

727044

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000107

AC:

119

AN:

1111726

Other (OTH)

AF:

0.0000663

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41462

American (AMR)

AF:

0.0000655

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.000142

Hom.:

Bravo

AF:

0.0000756

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:8Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:1Uncertain:4Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 28, 2022

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000527.5(LDLR):c.233G>A (p.Arg78His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PS4_Supporting and PP4 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: PM2 - PopMax MAF = 0.0001202 (0.012%) in African/African American exomes+genomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met. PP3 - REVEL = 0.806. It is above 0.75, so PP3 is met. PS4_supporting - variant meets PM2 and was identified in: - 1 index case with SB criteria of FH from PMID 31993549 (Garg et al., 2019), North America; - 1 index case with DLCN at least 8 (TC>10mmol/L and xanthomas) from PMID 27830735 (Jiang et al. 2016), China; - 1 index case with MEDPED criteria of FH from Benyahya et al. (2010) (paper cited in HGMD), Morocco; 3 unrelated index cases, so PS4_Supporting is met. PP4 - variant meets PM2 and was identified in 3 unrelated index cases who fulfill clinical criteria for FH after alternative causes of high cholesterol were excluded (please see PS4 for details), so PP4 is met. -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:literature only

- -

Dec 16, 2016

Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

subject mutated among 2600 FH index cases screened = 1 / patient compound heterozygous (LDLC max 400mg/dL) / Software predictions: Damaging -

Nov 30, 2023

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant (also known as p.Arg57His in the mature protein) replaces arginine with histidine at codon 78 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in 3 individuals affected with hypercholesterolemia (PMID 20809525; Benyahya et al., 2010, 31993549). This variant has also been reported in 11 UK Biobank participants who had normal or modestly elevated LDL-C levels (doi: 10.1101/2021.08.12.21261563). This variant has been identified in 15/282884 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Oct 12, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: LDLR c.233G>A (p.Arg78His) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251490 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (5.6e-05 vs 0.0013), allowing no conclusion about variant significance. c.233G>A has been reported in the literature in individuals from Myocardial infarction and Hypercholesterolemia cohort studies, however, case specific information (co-occurrences/co-segregation) was not available to evaluate causality (examples: Trinder_2022, Do_2015 and Marduel_2010). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. 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: 25487149, 31993549, 20809525, 34906840). Four submitters (including ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel) have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Dec 02, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in individuals with familial hypercholesterolemia and early myocardial infarction in published literature (PMID: 20809525, 25487149, 31993549; Benyahya F et al. (2010) The Journal of Applied Research. 10 (2):68-72); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R57H); This variant is associated with the following publications: (PMID: 32719484, 25487149, 20809525, Benyahya2010[CaseReport], 30415195, 31993549) -

Cardiovascular phenotype

Uncertain:1

May 16, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R78H variant (also known as c.233G>A), located in coding exon 3 of the LDLR gene, results from a G to A substitution at nucleotide position 233. The arginine at codon 78 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in familial hypercholesterolemia (FH) cohorts; however, clinical details were limited in some cases (Marduel M et al. Hum Mutat, 2010 Nov;31:E1811-24; Rieck L et al. Clin Genet, 2020 Nov;98:457-467). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Familial hypercholesterolemia

Uncertain:1

Feb 20, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with histidine at codon 78 of the LDLR protein. This variant is also known as p.Arg57His in the mature protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in four individuals affected with familial hypercholesterolemia (PMID: 20809525, 31993549, 32770674; Benyahya et al., 2010). This variant has also been reported in 11 UK Biobank participants who had normal or modestly elevated LDL-C levels (doi: 10.1101/2021.08.12.21261563). This variant has been identified in 15/282884 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.021

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.73

D;.;.;.;.

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.83

T;T;D;T;T

M_CAP

Pathogenic

0.42

MetaRNN

Benign

0.41

T;T;T;T;T

MetaSVM

Uncertain

0.35

MutationAssessor

Benign

1.1

L;.;L;L;L

PhyloP100

1.5

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-2.9

D;D;N;N;D

REVEL

Pathogenic

0.81

Sift

Benign

0.11

T;T;T;T;T

Sift4G

Benign

0.13

T;T;D;D;T

Polyphen

0.99

D;.;.;.;.

Vest4

0.20

MVP

1.0

MPC

0.34

ClinPred

0.074

GERP RS

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.37

gMVP

0.83

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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