rs748554592

Positions:

chr19-11113332-T-G

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: NM_000527.5(LDLR):c.1241T>G (p.Leu414Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PS4_supporting, PP3 and PP4) 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 = 0.0001088 (0.01088%) in East Asian exomes+genomes (gnomAD v2.1.1).PP3 - REVEL = 0.822.PS4_supporting - Variant meets PM2. Variant identified in 4 unrelated index cases (3 cases with Simon-Broome published in PMID:9763532; 1 case with DLCN criteria from Robarts Research Institute.PP4 - Variant meets PM2. Variant identified in 4 FH cases (3 cases with Simon-Broome Definite published in PMID:9763532; 1 case with DLCN criteria = > 6 from Robarts Research Institute. LINK:https://erepo.genome.network/evrepo/ui/classification/CA033186/MONDO:0007750/013

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:9U:1

Conservation

PhyloP100: 5.07

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 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.1241T>G	p.Leu414Arg	missense_variant	9/18	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.1241T>G	p.Leu414Arg	missense_variant	9/18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251172

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

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

AF:

0.00000342

AC:

AN:

1461584

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:9Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:4Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	Mar 13, 2019	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, 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	Mar 07, 2022	NM_000527.5(LDLR):c.1241T>G (p.Leu414Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PS4_supporting, PP3 and PP4) 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 = 0.0001088 (0.01088%) in East Asian exomes+genomes (gnomAD v2.1.1). PP3 - REVEL = 0.822. PS4_supporting - Variant meets PM2. Variant identified in 4 unrelated index cases (3 cases with Simon-Broome published in PMID: 9763532; 1 case with DLCN criteria from Robarts Research Institute. PP4 - Variant meets PM2. Variant identified in 4 FH cases (3 cases with Simon-Broome Definite published in PMID: 9763532; 1 case with DLCN criteria = > 6 from Robarts Research Institute. -

Familial hypercholesterolemia

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 22, 2019	This missense variant (also known as p.Leu393Arg in the mature protein) replaces leucine with arginine at codon 414 in the first EGF-like repeat B in the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 26608663, 26875521, 27765764, 29353225, 9763532). This variant has been identified in 2/251172 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 08, 2019	Variant summary: LDLR c.1241T>G (p.Leu414Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251172 control chromosomes. c.1241T>G has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Mak_1998, Kondkar_2007, Chiou_2017, Chan_2018, Pek_2018), predominantly in individuals from Asian origin. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions (evaluation after 2014) cite variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2023	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 414 of the LDLR protein (p.Leu414Arg). This variant is present in population databases (rs748554592, gnomAD 0.01%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 9452118, 27765764). This variant is also known as L393R. ClinVar contains an entry for this variant (Variation ID: 251747). 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%. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Sep 20, 2023

The LDLR c.1241T>G (p.Leu414Arg) variant has been reported in the published literature in multiple individuals affected with familial hypercholesterolemia (PMIDs: 9763532 (1998), 11005141 (2000), 18022922 (2007), 26875521 (2016), 30592178 (2019), 33994402 (2021), 35130036 (2022), 36229885 (2022), 36325061 (2022)). The frequency of this variant in the general population, 0.000008 (2/251172 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2023

The c.1241T>G (p.L414R) alteration is located in exon 9 (coding exon 9) of the LDLR gene. This alteration results from a T to G substitution at nucleotide position 1241, causing the leucine (L) at amino acid position 414 to be replaced by an arginine (R). Based on data from gnomAD, the G allele has an overall frequency of 0.001% (2/251172) total alleles studied. The highest observed frequency was 0.011% (2/18384) of East Asian alleles. This variant was identified in trans with a second LDLR variant in twins presenting with elevated LDL-C levels and multiple xanthomas (Zhang, 2022). In addition, this variant has been identified alone in multiple individuals with familial hypercholesterolemia (Mak, 1998; Mak, 1998; Kondkar, 2007; Chiou, 2017; Pek, 2018; Chan, 2019; Huang, 2022). This amino acid position is well conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.42

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;.;.;.;.;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D;D;D;D;D

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

0.83

MutationAssessor

Uncertain

2.2

M;.;.;.;.;M

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-5.6

D;D;D;D;D;D

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

0.95

P;.;.;.;.;.

Vest4

0.81

MutPred

0.88

Loss of stability (P = 0.0145);Loss of stability (P = 0.0145);.;.;.;Loss of stability (P = 0.0145);

MVP

1.0

MPC

0.94

ClinPred

0.97

GERP RS

3.9

Varity_R

0.82

gMVP

1.0

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