rs879254760

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3PP4PM5_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR):c.1028G>A (p.Gly343Asp) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PM5_Strong) 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: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL=0.959, it is above 0.75.PP4: Variant meets PM2 and is identified in 1 index case who fulfil DLCN criteria for definite FH after alternative causes of high cholesterol were excluded, reported in ClinVar (SCV000583778.1) from U4M - Lille University & CHRU Lille, Universite de Lille - CHRU de Lille, France.PM5_Strong: Three other variants at the same codon: NM_000527.5(LDLR):c.1028G>T (p.Gly343Val)(ClinVarID 440618) classified as Likely Pathogenic, NM_000527.5(LDLR):c.1027G>A (p.Gly343Ser)(ClinVarID 183106) is classified as Pathogenic, NM_000527.5(LDLR):c.1027G>T (p.Gly343Cys)(ClinVarID 251605) is classified as Pathogenic by these guidelines, therefore PM5_Strong is met.PS4 not met: Variant meets PM2 and is reported in 1 index case and family fulfil FH criteria, reported from U4M - Lille University & CHRU Lille, Universite de Lille - CHRU de Lille, France.PS3 not met: Functional data is not available. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585258/MONDO:0007750/013

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:4

Conservation

PhyloP100: 9.65

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

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

PM5

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.1028G>A	p.Gly343Asp	missense_variant	7/18	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.1028G>A	p.Gly343Asp	missense_variant	7/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461478

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727050

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:3

Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jan 27, 2023	The NM_000527.5 (LDLR):c.1028G>A (p.Gly343Asp) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PM5_Strong) 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: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL=0.959, it is above 0.75. PP4: Variant meets PM2 and is identified in 1 index case who fulfil DLCN criteria for definite FH after alternative causes of high cholesterol were excluded, reported in ClinVar (SCV000583778.1) from U4M - Lille University & CHRU Lille, Universite de Lille - CHRU de Lille, France. PM5_Strong: Three other variants at the same codon: NM_000527.5(LDLR):c.1028G>T (p.Gly343Val)(ClinVarID 440618) classified as Likely Pathogenic, NM_000527.5(LDLR):c.1027G>A (p.Gly343Ser)(ClinVarID 183106) is classified as Pathogenic, NM_000527.5(LDLR):c.1027G>T (p.Gly343Cys)(ClinVarID 251605) is classified as Pathogenic by these guidelines, therefore PM5_Strong is met. PS4 not met: Variant meets PM2 and is reported in 1 index case and family fulfil FH criteria, reported from U4M - Lille University & CHRU Lille, Universite de Lille - CHRU de Lille, France. PS3 not met: Functional data is not available. -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2019

The p.G343D variant (also known as c.1028G>A), located in coding exon 7 of the LDLR gene, results from a G to A substitution at nucleotide position 1028. The glycine at codon 343 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been detected in an individual with familial hypercholesterolemia (FH) (Amsellem S et al. Hum. Genet., 2002 Dec;111:501-10). In addition, a different alteration located at the same position, p.G343S, has been reported in a number of individuals with familial hypercholesterolemia (Hobbs HH et al. Hum Mutat. 1992;1:445-66; Reshef A et al. Hum Genet. 1996;98:581-6; Thiart R et al. Mol Cell Probes. 2000;14:299-304; Fouchier SW et al. Hum Genet. 2001;109:602-15; Nissen H et al. Clin Genet. 1998;54:79-82; Mozas P et al. Hum Mutat. 2004;24:187; Bourbon M et al. Atherosclerosis. 2008;196:633-42; Bertolini S et al. Atherosclerosis. 2013;227:342-8; Huijgen R et al. Circ Cardiovasc Genet. 2011;4:413-7; Hooper AJ et al. Atherosclerosis. 2012;224:430-4), and reduced LDLR activity was revealed in some of those individuals (Hobbs HH et al. Hum Mutat. 1992;1:445-66; Thiart R et al. Mol Cell Probes. 2000;14:299-304). In addition, an in vitro study suggested that the p.G343S alteration would interfere with protein folding and thus surface expression (Boswell EJ et al. J Biol Chem. 2004;279:30611-21). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, the p.G343D variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;.;.;.;.;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

1.0

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.1

M;.;.;.;.;M

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-6.8

D;D;D;D;D;D

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0010

D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.94

MutPred

0.96

Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);.;.;.;Gain of relative solvent accessibility (P = 0.0215);

MVP

1.0

MPC

0.88

ClinPred

1.0

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.97

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