chr19-11113368-T-G

Position:

• chr19-11113368-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS4_Supporting PP3 PP4 PP1 PM2

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1277T>G (p.Leu426Arg) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP1, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on January 31, 2025.The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v4.1.0). PP3: REVEL= 0.907. It is above 0.75, so PP3 is met. PS4_Supporting, PP4: Variant meets PM2. Identified in 3 unrelated cases (1 case from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France with possible FH by Simon Broome criteria; 1 case with DLCN score of 6 from Lille University & CHRU Lille, France; 1 case with definite FH by Simon Broome criteria from Centre Hospitalo-Universitaire Xavier Bichat, Paris, France).PP1: Variant segregates with FH phenotype in 2 informative meioses identified by Centre Hospitalo-Universitaire Xavier Bichat, Paris. LINK:https://erepo.genome.network/evrepo/ui/classification/CA404084869/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 29)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4
• Conservation: PhyloP100: 6.18

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 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.
• PP1: 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	c.1277T>G	p.Leu426Arg	missense_variant	9/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1277T>G	p.Leu426Arg	missense_variant	9/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 29

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	May 24, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Sep 23, 2021	The c.1277T>G (p.Leu426Arg) variant identified in the LDLR gene has been reported in a patient with a family history of hypercholesterolemia (PMID:28353356). This variant is absent in gnomAD v.3.1.1, suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be deleterious to the function of the canonical transcript. This variant is reported as a Variant of Uncertain Significance and Likely Pathogenic inClinVar (VarID:1120245). An allelic variant c.1277T>C (p.Leu426Pro) has been reported in individual(s) with familial hypercholesterolemia (PMID: 9763532, 25775905).Based on the available evidence, the c.1277T>G (p.Leu426Arg) variant identified in the LDLR gene is reported as a Variant of UncertainSignificance. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 07, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 03, 2024	The LDLR c.1277T>G (p.Leu426Arg) variant has been reported in the published literature in individuals affected with hypercholesterolemia (PMIDs: 28353356 (2017), 34297352 (2021), 35379577 (2022)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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, we are unable to determine the clinical significance of this variant. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2018

The p.L426R variant (also known as c.1277T>G), located in coding exon 9 of the LDLR gene, results from a T to G substitution at nucleotide position 1277. The leucine at codon 426 is replaced by arginine, an amino acid with dissimilar properties. Another alteration affecting this amino acid (p.L426P c.1277T>C), referred to as L405P, has been previously reported in association with familial hypercholesterolemia (Mak YT et al. Arterioscler Thromb Vasc Biol. 1998;18(10):1600-5). Based on internal structural analysis, the p.L426R alteration lies in the YWTD β propeller at the interface with PCSK9 and is predicted to destabilize the domain (Lo Surdo P et al. EMBO Rep. 2011;12(12):1300-5). 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, this variant is likely to be pathogenic. -

Familial hypercholesterolemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 06, 2025

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 426 of the LDLR protein (p.Leu426Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 28353356). ClinVar contains an entry for this variant (Variation ID: 1120245). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.Leu426 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 9763532, 28353356, 33269076), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.;.;.;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M;.;.;.;.;M
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.4	D;D;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D
Polyphen		0.94	P;.;.;.;.;.
Vest4		0.84
MutPred		0.63		Loss of stability (P = 0.0049);Loss of stability (P = 0.0049);.;.;.;Loss of stability (P = 0.0049);
MVP		1.0
MPC		0.95
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.95
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-11224044;