rs879254938

Positions:

chr19-11113729-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP4PS4_SupportingBP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR):c.1553A>G (p. Lys518Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PS4_Supporting, BP4) 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 = 0.00001 in European (Non-Finnish) population in gnomAD (gnomAD v2.1.1).PP4: Variant meets PM2 and is identified in ˃1 index case who fulfil criteria for FH diagnosis from 2 labs after alternative causes of high cholesterol were excluded. PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated index cases who fulfil FH diagnosis criteria. One index case met MedPed definite FH criteria from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); one index case fulfil Simon Broome criteria for FH, reported by Usifo et al, 2012, British Heart Foundation Laboratories, Centre for Cardiovascular Genetics, Institute of Cardiovascular Sciences, University College London, London, UK (PMID22881376). BP4: REVEL = 0.371, it is below 0.5, splicing evaluation required. Variant is exonic and is not on limit creating de novo acceptor site. It is located at least 50bp downstream from canonical acceptor site but does not create GT. Variant is not predicted to alter splicing.PP3 not met: REVEL = 0.371, it is not above 0.75. Alternative splicing is not predicted.PS3 not met: Functional data on splicing is not available.PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.1552A>G (p.Lys518Glu) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585500/MONDO:0007750/013

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:4B:1

Conservation

PhyloP100: 3.72

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 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.

BP4

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.1553A>G	p.Lys518Arg	missense_variant	10/18	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.1553A>G	p.Lys518Arg	missense_variant	10/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251378

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727230

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:

0.00000989

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant replaces lysine with arginine at codon 518 of the LDLR protein. This variant is also known as p.Lys497Arg in the mature protein. This variant alters a conserved lysine residue in the LDLR type B repeat 3 of the EGF precursor homology domain in the LDLR protein (a.a. 486 - 528), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with familial hypercholesterolemia (PMID: 22881376; Color internal data). This variant has been identified in 1/251378 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. -
Likely benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Aug 26, 2022	The NM_000527.5 (LDLR):c.1553A>G (p. Lys518Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PS4_Supporting, BP4) 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 = 0.00001 in European (Non-Finnish) population in gnomAD (gnomAD v2.1.1). PP4: Variant meets PM2 and is identified in ˃1 index case who fulfil criteria for FH diagnosis from 2 labs after alternative causes of high cholesterol were excluded. PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated index cases who fulfil FH diagnosis criteria. One index case met MedPed definite FH criteria from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); one index case fulfil Simon Broome criteria for FH, reported by Usifo et al, 2012, British Heart Foundation Laboratories, Centre for Cardiovascular Genetics, Institute of Cardiovascular Sciences, University College London, London, UK (PMID22881376). BP4: REVEL = 0.371, it is below 0.5, splicing evaluation required. Variant is exonic and is not on limit creating de novo acceptor site. It is located at least 50bp downstream from canonical acceptor site but does not create GT. Variant is not predicted to alter splicing. PP3 not met: REVEL = 0.371, it is not above 0.75. Alternative splicing is not predicted. PS3 not met: Functional data on splicing is not available. PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.1552A>G (p.Lys518Glu) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2019

- -

Familial hypercholesterolemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 12, 2023

This missense variant replaces lysine with arginine at codon 518 of the LDLR protein. This variant is also known as p.Lys497Arg in the mature protein. This variant alters a conserved lysine residue in the LDLR type B repeat 3 of the EGF precursor homology domain in the LDLR protein (a.a. 486 - 528), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with familial hypercholesterolemia (PMID: 22881376; Color internal data). This variant has been identified in 1/251378 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

0.095

BayesDel_addAF

Uncertain

0.091

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.73

D;.;.;.;.;.

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.47

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.80

T;T;T;T;T;T

M_CAP

Pathogenic

0.48

MetaRNN

Uncertain

0.64

D;D;D;D;D;D

MetaSVM

Uncertain

0.46

MutationAssessor

Benign

1.4

L;.;.;.;.;L

MutationTaster

Benign

0.76

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

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.8

N;N;N;N;N;N

REVEL

Uncertain

0.37

Sift

Benign

0.091

T;T;T;T;T;T

Sift4G

Benign

0.063

T;T;T;T;T;T

Polyphen

0.014

B;.;.;.;.;.

Vest4

0.15

MVP

1.0

MPC

0.25

ClinPred

0.28

GERP RS

2.6

Varity_R

0.22

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