rs370860696

Positions:

chr19-11102705-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP4PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.232C>T (p.Arg78Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PS4_Supporting and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.0001002 (0.010%) in South Asian exomes (gnomAD v2.1.1).PP4 - Variant meets PM2. Identified in 2 FH cases from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with Dutch Lipid Clinic score ≥ 6. PS4_supporting - Variant meets PM2. Variant identified in at least 4 unrelated index cases with Simon-Broome criteria for FH or Dutch Lipid Clinic score equal or above 6 from different labs. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023658/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:2U:11

Conservation

PhyloP100: 3.09

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:

LDLR (HGNC:):

LDLR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 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.

PP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.232C>T	p.Arg78Cys	missense_variant	3/18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.232C>T	p.Arg78Cys	missense_variant	3/18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251492

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000534

AC:

AN:

1461644

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000576

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000585

Hom.:

Bravo

AF:

0.0000264

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:2Uncertain:3

Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Nov 29, 2010	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 07, 2021	The NM_000527.5(LDLR):c.232C>T (p.Arg78Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PS4_Supporting and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.0001002 (0.010%) in South Asian exomes (gnomAD v2.1.1). PP4 - Variant meets PM2. Identified in 2 FH cases from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with Dutch Lipid Clinic score ≥ 6. PS4_supporting - Variant meets PM2. Variant identified in at least 4 unrelated index cases with Simon-Broome criteria for FH or Dutch Lipid Clinic score equal or above 6 from different labs. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 17, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 29, 2024	This missense variant (also known as p.Arg57Cys in the mature protein) replaces arginine with cysteine at codon 78 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 9259195, 9664576, 24956927, 32522009). This variant has been identified in 8/282882 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. -

Familial hypercholesterolemia

Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 07, 2020	- -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Arg78Cys variant in LDLR has been reported in at least 9 individuals with familial hypercholesterolemia (PMID: 9259195, 28502495, 11845603, 9664576, 22883975, 24956927, 27680772) and has been Identified in 0.01002% (2/19952) of East Asian chromosomes, and at lower frequencies in other populations, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs370860696). This variant has also been reported in ClinVar (VariationID: 161289) as likely pathogenic by the British Heart Foundation, pathogenic by Fiona Stanley Hospital, and as a VUS by the University of Washington Medical Center. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_moderate (Richards 2015). -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 27, 2023	This missense variant (also known as p.Arg57Cys in the mature protein) replaces arginine with cysteine at codon 78 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 9259195, 9664576, 24956927, 32522009). This variant has been identified in 8/282882 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 02, 2021	This sequence change replaces arginine with cysteine at codon 78 of the LDLR protein (p.Arg78Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs370860696, ExAC 0.01%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 9237502, 9259195, 9664576, 22883975, 22910581, 24956927). This variant is also known as R57C. ClinVar contains an entry for this variant (Variation ID: 161289). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 09, 2024

Variant summary: LDLR c.232C>T (p.Arg78Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251492 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.232C>T has been reported in the literature in the heterozygous tate in individuals affected with Familial Hypercholesterolemia (Kotze_1997, Day_1997, Callis_1998, Hooper_2012, Norsworthy_2014). 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. This variant is also known as R57C. The following publications have been ascertained in the context of this evaluation (PMID: 9664576, 9259195, 22883975, 22910581, 9237502, 24956927). ClinVar contains an entry for this variant (Variation ID: 161289). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hypercholesterolemia

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

not provided

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The LDLR p.Arg78Cys variant was identified in 2 of 1606 proband chromosomes (frequency: 0.001) from individuals with familial hypercholesterolemia (FH) (Callis_1998_PMID:9664576; Day_1997_PMID:9259195). The variant was also identified in 1 of 232 individuals from a Scottish cohort with moderately high total cholesterol despite cholesterol-lowering therapy but was not identified in 192 controls or 193 individuals with high cholesterol (Norsworthy_2014_PMID:24956927). In a family with FH, the p.A78C variant was identified in the mother with classical heterozygous FH who also carried a deletion of exons 2-5 of the LDLR gene. The father carried the exon 2-5 deletion as well as another intronic LDLR variant and also presented with classical heterozygous FH. The child was homozygous for the exon 2-5 deletion and presented with classical homozygous FH, suggesting that the exon 2-5 deletion was the cause of disease in this family and that the p.A78C variant likely does not contribute to disease in the mother (Jelassi_2012_PMID:22910581). The variant was identified in dbSNP (ID: rs370860696), LOVD 3.0 and ClinVar (classified as a VUS by CSER_CC_NCGL; University of Washington Medical Center, likely pathogenic by LDLR-LOVD, British Heart Foundation and pathogenic by Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital). The variant was identified in control databases in 8 of 282882 chromosomes at a frequency of 0.000028 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 2 of 19952 chromosomes (freq: 0.0001), South Asian in 2 of 30616 chromosomes (freq: 0.000065), African in 1 of 24968 chromosomes (freq: 0.00004) and European (non-Finnish) in 3 of 129190 chromosomes (freq: 0.000023), but was not observed in the Latino, Ashkenazi Jewish, European (Finnish) or Other populations. The p.Arg78 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 27, 2024

The c.232C>T (p.R78C) alteration is located in exon 3 (coding exon 3) of the LDLR gene. This alteration results from a C to T substitution at nucleotide position 232, causing the arginine (R) at amino acid position 78 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

D;.;.;.;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.87

D;D;D;T;D

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.86

D;D;D;D;D

MetaSVM

Pathogenic

0.83

MutationAssessor

Uncertain

2.3

M;.;M;M;M

PrimateAI

Benign

0.32

PROVEAN

Pathogenic

-4.8

D;D;D;D;D

REVEL

Pathogenic

0.71

Sift

Uncertain

0.016

D;D;D;D;D

Sift4G

Uncertain

0.055

T;D;D;D;T

Polyphen

1.0

D;.;.;.;.

Vest4

0.69

MVP

1.0

MPC

0.92

ClinPred

0.81

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.62

gMVP

0.94

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