19-11113543-T-C

Position:

chr19-11113543-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3PP4PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR):c.1367T>C (p.Leu456Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023.The supporting evidence is as follows:PM2: PopMax MAF=0.00006 in African population in gnomAD (gnomAD 2.1.1).PP3: REVEL=0.862.PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 2 unrelated index cases who fulfill criteria for FH (1 case meeting Simon Broome criteria from UT Southwestern Medical Center, US, in PMID 23064986 (Ahmad et al., 2012); 1 case from University of Pennsylvania, US, in PMID 19026292 (Kolansky et al., 2008) with total cholesterol of 836 mg/dl at age of 8 yrs and pathogenic LDLR variant c.1846-1G>A. LINK:https://erepo.genome.network/evrepo/ui/classification/CA305300092/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:2U:4

Conservation

PhyloP100: 7.79

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:

MIR6886 (HGNC:):

MIR6886 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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.

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.1367T>C	p.Leu456Pro	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.1367T>C	p.Leu456Pro	missense_variant	10/18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250860

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135670

show subpopulations

Gnomad AFR exome

AF:

0.0000617

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:1Uncertain:1

Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 23, 2024	The NM_000527.5 (LDLR):c.1367T>C (p.Leu456Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023. The supporting evidence is as follows: PM2: PopMax MAF=0.00006 in African population in gnomAD (gnomAD 2.1.1). PP3: REVEL=0.862. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 2 unrelated index cases who fulfill criteria for FH (1 case meeting Simon Broome criteria from UT Southwestern Medical Center, US, in PMID 23064986 (Ahmad et al., 2012); 1 case from University of Pennsylvania, US, in PMID 19026292 (Kolansky et al., 2008) with total cholesterol of 836 mg/dl at age of 8 yrs and pathogenic LDLR variant c.1846-1G>A. -

Familial hypercholesterolemia

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 16, 2023	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 456 of the LDLR protein (p.Leu456Pro). This variant is present in population databases (rs200143634, gnomAD 0.007%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 19026292, 23064986). This variant is also known as L435P. ClinVar contains an entry for this variant (Variation ID: 440637). 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. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 12, 2023	This missense variant (also known as p.Leu435Pro in the mature protein) replaces leucine with proline at codon 456 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 at least one individual affected with familial hypercholesterolemia (PMID: 23064986). This variant has also been observed in compound heterozygous state in an individual affected with homozygous familial hypercholesterolemia (PMID: 19026292), indicating that this variant contributes to disease. This variant has been identified in 1/250860 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

AiLife Diagnostics, AiLife Diagnostics

Sep 07, 2021

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 31, 2023

The p.L456P variant (also known as c.1367T>C), located in coding exon 10 of the LDLR gene, results from a T to C substitution at nucleotide position 1367. The leucine at codon 456 is replaced by proline, an amino acid with similar properties. This variant, also referred to as p.L435P, has been detected in an individual with untreated LDL-C of 279mg/dL, and co-occurred with a canonical LDLR variant in second individual reported to have homozygous familial hypercholesterolemia (Ahmad Z et al. Circ Cardiovasc Genet, 2012 Dec;5:666-75; Kolansky DM et al. Am J Cardiol, 2008 Dec;102:1438-43). This amino acid position is poorly 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

Benign

0.28

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

D;.;.;.;.;.

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.80

T;T;T;T;T;T

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Benign

2.0

M;.;.;.;.;M

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-4.9

D;D;D;D;D;D

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0010

D;D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D

Polyphen

0.68

P;.;.;.;.;.

Vest4

0.51

MutPred

0.93

Gain of disorder (P = 0.0095);Gain of disorder (P = 0.0095);.;.;.;Gain of disorder (P = 0.0095);

MVP

1.0

MPC

0.97

ClinPred

0.98

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.81

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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