rs544453230

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS3_SupportingPM2PP3PP4PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1003G>A (p.Gly335Ser) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PP4, PS3_Supporting and PS4_Supporting 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 = 0.00005431 (0.005431%) in European non-Finnish exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met.PP3 - REVEL = 0.843. It is above 0.75, so PP3 is met.PS4_supporting - variant meets PM2 and was identified in:- 3 unrelated index cases who fulfill Dutch lipid clinic network >=6 from Robarts Research Institute, Canada;- at least 1 index case with Dutch Lipid Clinic Scoring : Definite FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583773.1), France;- 1 index case with DLNC > or = 6 from Bañares et al. 2017 (PMID:28502510), Argentina;at least 5 unrelated index cases with clinical FH criteria, so PP4 is met.PP4 - variant meets PM2 and was identified in at least 5 unrelated index cases with clinical FH criteria (see PS4_Supporting for details), so PP4 is met.PS3_supporting - Level 3 FS: Hobbs et al. 1992 (PMID:1301956): Heterozygous patients' fibroblasts, 125I-LDL assays - results: 30-40% LDLR activity.--- activity is below 85% of wild-type, so PS3_Supporting is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023402/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

9

4

6

Clinical Significance

Likely pathogenic reviewed by expert panel P:17U:1B:1O:1

Conservation

PhyloP100: 9.68

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 Likely_pathogenic. Variant got 6 ACMG points.

PS3

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

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/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.1003G>A	p.Gly335Ser	missense_variant	7/18	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.1003G>A	p.Gly335Ser	missense_variant	7/18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

7

AN:

152150

Hom.:

0

Cov.:

32

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:

0.000577

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

7

AN:

251016

Hom.:

0

AF XY:

0.0000368

AC XY:

5

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

21

AN:

1461548

Hom.:

0

Cov.:

31

AF XY:

0.0000151

AC XY:

11

AN XY:

727068

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

7

AN:

152268

Hom.:

0

Cov.:

32

AF XY:

0.0000537

AC XY:

4

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000279

Hom.:

0

Bravo

AF:

0.0000189

TwinsUK

AF:

0.000270

AC:

1

ALSPAC

AF:

0.00

AC:

0

ExAC

AF:

0.0000494

AC:

6

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:17Uncertain:1Benign:1Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:11Benign:1

Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Apr 28, 2023	The NM_000527.5(LDLR):c.1003G>A (p.Gly335Ser) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PP4, PS3_Supporting and PS4_Supporting 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 = 0.00005431 (0.005431%) in European non-Finnish exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met. PP3 - REVEL = 0.843. It is above 0.75, so PP3 is met. PS4_supporting - variant meets PM2 and was identified in: - 3 unrelated index cases who fulfill Dutch lipid clinic network >=6 from Robarts Research Institute, Canada; - at least 1 index case with Dutch Lipid Clinic Scoring : Definite FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583773.1), France; - 1 index case with DLNC > or = 6 from Bañares et al. 2017 (PMID: 28502510), Argentina; at least 5 unrelated index cases with clinical FH criteria, so PP4 is met. PP4 - variant meets PM2 and was identified in at least 5 unrelated index cases with clinical FH criteria (see PS4_Supporting for details), so PP4 is met. PS3_supporting - Level 3 FS: Hobbs et al. 1992 (PMID: 1301956): Heterozygous patients' fibroblasts, 125I-LDL assays - results: 30-40% LDLR activity. --- activity is below 85% of wild-type, so PS3_Supporting is met. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Mar 08, 2024	This missense variant (also known as p.Gly314Ser in the mature protein and as FH Paris-6) replaces glycine with serine at codon 335 in the EGF precursor homology domain 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). Functional studies have shown the mutant protein to exhibit normal LDLR activity in an in vitro high throughput cell-based assay (PMID: 25647241) and mildly reduced activity (30-40% of normal activity) in ex vivo assays using cells from a compound heterozygous carrier (PMID: 1301956). This LDLR variant has been reported in over 10 heterozygous individuals affected with familial hypercholesterolemia (PMID: 1301956, 11668627, 15556094, 23375686, 27765764, 28008010, 28502510, 33740630, 34297352). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in two related individuals affected with homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 27578127). This variant has been identified in 8/282406 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely benign, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	subject mutated among 2600 FH index cases screened = 1 / Software predictions: Damaging -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	May 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Likely pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Oct 31, 2014	- -
Likely pathogenic, criteria provided, single submitter	curation;literature only	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 16, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PS4_Moderate+PP1+PP4+PP3 -

Familial hypercholesterolemia

Pathogenic:4Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Sep 24, 2019	This variant has been previously reported as a heterozygous change in patients with familial hypercholesterolemia (PMID: 1301956, 23375686). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0028% (8/282,406) and thus is presumed to be rare. The c.1003G>A (p.Gly335Ser) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1003G>A (p.Gly335Ser) variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	Aug 06, 2021	- -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Gly335Ser variant in LDLR has been reported in at least 6 individuals with familial hypercholesterolemia (PMID: 1301956, 11668627, 15556094, 27765764, 27578127, 28008010, 2852510) and has been identified in 0.005431% (7/128886) of European (non-Finnish) chromosomes and 0.005016% (1/19938) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs544453230). This variant has also been reported in ClinVar (PMID: 183105) as likely benign by Centre de Genetique Moleculaire et Chromosomique, as a VUS by the Laboratory for Molecular Medicine, as likely pathogenic by the British Heart Foundation, Roberts Research Institute, Instituto Nacional de Saude Doutor Ricardo Jorge, Iberoamerican FH Network, Invitae, and the Children's Hospital of Philadelphia, and as Pathogenic by U4M - Lille University & CHRU Lille. In vitro functional studies provide some evidence that the p.Gly335Ser variant may not impact protein function (PMID: 25647241). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. 4 affected individuals with this variant have an alternative molecular basis for familial hypercholesterolemia , suggesting that this variant may not be pathogenic (PMID: 27578127). In summary, the clinical significance of the p.Gly335Arg variant is uncertain. ACMG/AMP Criteria applied: PS4_moderate, PP3, BP5, BS3_supporting (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 02, 2024	This missense variant replaces glycine with serine at codon 335 in the EGF precursor homology domain of the LDLR protein. This variant is also known as p.Gly314Ser in the mature protein, and as and as FH Paris-6 in the literature. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Functional studies have shown the mutant protein to exhibits normal LDLR activity in an in vitro high throughput cell-based assay (PMID: 25647241) and mildly reduced activity (30-40% of normal activity) in ex vivo assays using cells from a compound heterozygous carrier individual (PMID: 1301956). This LDLR variant has been reported in over 10 heterozygous individuals affected with familial hypercholesterolemia (PMID: 1301956, 11668627, 15556094, 23375686, 27765764, 28008010, 28502510, 33740630, 34297352). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in two related individuals affected with homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 27578127). This variant has been identified in 8/282406 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 29, 2023	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 335 of the LDLR protein (p.Gly335Ser). This variant is present in population databases (rs544453230, gnomAD 0.006%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1301956, 11668627, 15556094, 23375686, 27765764, 28502510). This variant is also known as Gly314Ser. ClinVar contains an entry for this variant (Variation ID: 183105). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LDLR function (PMID: 1301956, 25647241). This variant disrupts the p.Gly335 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 10735632), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Homozygous familial hypercholesterolemia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 22, 2021

The p.Gly335Ser variant in LDLR (also described as p.Glu314Ser in the literature) has been reported in at least 14 individuals with hypercholesterolemia: in at least 11 heterozygotes, 1 double heterozygote who also had a pathogenic variant in the PCSK9 gene, and in the compound heterozygous state with another pathogenic LDLR variant in a set of identical twins with homozygous familial hypercholesterolemia (HoFH; Hobbs 1992 PMID: 1301956, Wang 2001 PMID: 11668627, Laurie 2004 PMID: 15556094, Bertolini 2013 PMID: 23375686, Retterer 2015 PMID: 26633542, Abul-Husn 2016 PMID: 28008010, Rabacchi 2016 PMID: 27578127, Wang 2015 PMID: 27765764, Banares 2017 PMID: 28502510, Clinvar Variation ID 183105). It has also been identified in 2 individuals with myocardial infarction (Do 2015 PMID: 25487149, Thomaehlen 2015 PMID: 25647241). In the family with HoFH, this variant segregated with disease (in the compound heterozygous state) in 2 other affected siblings and in the heterozygous state in 2 other affected relatives (Rabacchi 2016 PMID: 27578127). Functional studies provide conflicting evidence on the impact of this variant on the protein (Hobbs 1992 PMID: 1301956, Thormaehlen 2015 PMID: 25647241). Additionally, this variant has been identified in 0.005% (7/128886) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of familial hypercholesterolemia (FH) in the general population. Computational prediction tools and conservation analysis are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PM3, PS4_Moderate, PP1, PP3, PM2_Supporting. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 26, 2024

The c.1003G>A (p.G335S) alteration is located in exon 7 (coding exon 7) of the LDLR gene. This alteration results from a G to A substitution at nucleotide position 1003, causing the glycine (G) at amino acid position 335 to be replaced by a serine (S). Based on data from gnomAD, the A allele has an overall frequency of 0.003% (8/282406) total alleles studied. The highest observed frequency was 0.005% (7/128886) of European (non-Finnish) alleles. This alteration (legacy nomenclature G314S) has been reported in multiple individuals with concerns for familial hypercholesterolemia (FH) (Hobbs, 1992; Laurie, 2004; Bertolini, 2013; Retterer, 2016; Wang, 2016; Bañares, 2017; Martín-Campos, 2018; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. Internal structural analysis suggests that this variant is anticipated to disrupt a region of known function (Rudenko, 2002; Lo Surdo, 2011). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

not provided

Other:1

not provided, no classification provided

in vitro

Dept. of Genetics and Pharmacogenomics, Merck Research Labs

-

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.39

D

BayesDel_noAF

Pathogenic

0.49

CADD

Uncertain

26

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;.;.;.;.;.

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

1.0

D

LIST_S2

Uncertain

0.96

D;D;D;D;D;D

M_CAP

Pathogenic

0.50

D

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

D

MutationAssessor

Benign

0.77

N;.;.;.;.;N

PrimateAI

Benign

0.47

T

PROVEAN

Pathogenic

-5.7

D;D;D;D;D;D

REVEL

Pathogenic

0.84

Sift

Benign

0.087

T;T;T;D;T;T

Sift4G

Benign

0.15

T;T;T;T;T;T

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.84

MutPred

0.88

Gain of ubiquitination at K333 (P = 0.1132);Gain of ubiquitination at K333 (P = 0.1132);.;.;.;Gain of ubiquitination at K333 (P = 0.1132);

MVP

1.0

MPC

0.76

ClinPred

0.92

D

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.70

gMVP

0.92

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.

Other links and lift over

dbSNP: rs544453230; hg19: chr19-11221390;