19-11113743-G-C

Position:

chr19-11113743-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3PP4PM5

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR): c.1567G>C (p.Val523Leu) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM5, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 January 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.00003 in South Asian exomes (gnomAD v2.1.1).PP3: REVEL = 0.904. PM5: There is 1 missense variant in the same codon, NM_000527.5(LDLR):c.1567G>A (p.Val523Met), classified as Pathogenic by these guidelines.PP4: Variant meets PM2 and is identified in 1 patient with possible FH by Simon Broome criteria from PMID 26748104 (Reiman et al., 2016). LINK:https://erepo.genome.network/evrepo/ui/classification/CA034835/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., 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:2U:3

Conservation

PhyloP100: 8.02

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 Likely_pathogenic. Variant got 6 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.1567G>C	p.Val523Leu	missense_variant	10/18	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.1567G>C	p.Val523Leu	missense_variant	10/18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251336

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135872

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461630

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727128

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2Uncertain:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Familial hypercholesterolemia

Pathogenic:1Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham	Aug 03, 2023	This variant located in exon 10 of the LDLR gene, results from a G to C substitution at nucleotide position 1567.This variant and another variant resulting in the same amino acid change (c.1567G>T) have been reported in familial hypercholesterolemia cohorts. Another alteration at the same codon, p.V523M (c.1567G>A), has been been reported in the homozygous and heterozygous states in multiple individuals with familial hypercholesterolemia -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 07, 2023	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Val523 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2088165, 14974088, 15256764, 21310417, 21865347, 22294733, 23375686, 25463123, 27765764). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 993226). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolaemia (PMID: 26748104). This variant is present in population databases (rs28942080, gnomAD 0.003%). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 523 of the LDLR protein (p.Val523Leu). -

Hypercholesterolemia, familial, 1

Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Jan 27, 2024

The NM_000527.5(LDLR): c.1567G>C (p.Val523Leu) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM5, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 January 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.00003 in South Asian exomes (gnomAD v2.1.1). PP3: REVEL = 0.904. PM5: There is 1 missense variant in the same codon, NM_000527.5(LDLR):c.1567G>A (p.Val523Met), classified as Pathogenic by these guidelines. PP4: Variant meets PM2 and is identified in 1 patient with possible FH by Simon Broome criteria from PMID 26748104 (Reiman et al., 2016). -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Dec 13, 2019

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2023

The p.V523L variant (also known as c.1567G>C), located in coding exon 10 of the LDLR gene, results from a G to C substitution at nucleotide position 1567. The valine at codon 523 is replaced by leucine, an amino acid with highly similar properties. This variant and another variant resulting in the same amino acid change (c.1567G>T) have been reported in familial hypercholesterolemia cohorts, but clinical details were limited (Marduel M et al. Hum Mutat, 2010 Nov;31:E1811-24; Pandey S et al. J Appl Lab Med, 2016 Sep;1:109-118; Reiman A et al. Ann Clin Biochem, 2016 Nov;53:654-662; Leren TP et al. Atherosclerosis, 2021 Apr;322:61-66). Another alteration at the same codon, p.V523M (c.1567G>A), has been been reported in the homozygous and heterozygous states in multiple individuals with familial hypercholesterolemia (e.g., Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Lombardi P et al. J. Lipid Res., 1995 Apr;36:860-7; Luirink IK et al. J Clin Lipidol Dec;13:272-278). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.45

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.79

D;.;.;.;.;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D;D;D;D

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

M;.;.;.;.;M

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.9

N;N;N;N;N;N

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0030

D;D;D;D;D;D

Sift4G

Uncertain

0.012

D;D;D;D;D;D

Polyphen

0.21

B;.;.;.;.;.

Vest4

0.63

MutPred

0.89

Loss of methylation at K518 (P = 0.089);Loss of methylation at K518 (P = 0.089);.;.;.;Loss of methylation at K518 (P = 0.089);

MVP

1.0

MPC

0.48

ClinPred

0.92

GERP RS

4.7

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.74

gMVP

0.99

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