rs774723292

chr19-11105249-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000527.5(LDLR):c.343C>T(p.Arg115Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R115H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:12 U:4
• Conservation: PhyloP100: 1.58

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 8 uncertain in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-11105250-G-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894
• PP5: Variant 19-11105249-C-T is Pathogenic according to our data. Variant chr19-11105249-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251162.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-11105249-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.343C>T	p.Arg115Cys	missense_variant	4/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.343C>T	p.Arg115Cys	missense_variant	4/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000279 AC: 7 AN: 250716 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135750

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461240 Hom.: 0 Cov.: 33 AF XY: 0.0000206 AC XY: 15 AN XY: 726948

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000268 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:12 Uncertain:4

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:9 Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2023	This missense variant replaces arginine with cysteine at codon 115 of the LDLR protein. This variant is also known as p.Arg94Cys in the mature protein. This variant is located in the type A repeat 3 ligand binding domain (aa 107-145) 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). A functional study using a pig model has shown that this variant disrupts LDLR activity (PMID: 10064736). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 16250003, 30270359, 34074024, 33418990) in the literature, including three hypercholesterolemic individuals in one family (PMID: 30270359). This variant has also been reported in affected individuals by external laboratories (ClinVar submission SCV000583664.1, SCV000503143.1, SCV001482448.1). This variant has been identified in 7/250716 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 12, 2023	The LDLR c.343C>T (p.Arg115Cys) missense variant has been identified in individuals with familial hypercholesterolemia; however, clinical details are limited (PMID:16250003;33418990). This variant is located in the LDLR class A repeat, a component of the well-established ligand (LDL) binding domain within exon 4. The p.Arg115Cys variant results in a substitution of arginine by cysteine, which may affect disulfide bond formation and protein folding (PMID: 34906454). This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Multiple lines of computational evidence suggest the variant may impact the gene or gene product. The p.Arg115Cys variant has been classified as likely pathogenic by at least three submitters in ClinVar including the ClinGen familial hypercholesterolemia variant curation expert panel. Based on the available evidence, the c.343C>T (p.Arg115Cys) variant is classified as likely pathogenic for familial hypercholesterolemia. -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jan 07, 2021	ACMG classification criteria: PS4, PM2, PP1, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 25, 2021	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 07, 2021	The NM_000527.5(LDLR):c.343C>T (p.Arg115Cys) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM1, PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM1 - Missense at codon 115. Variant meets PM2 and is in exon 4. PM2 - FAF = 0.0001446 (0.014%) in Latino/Admixed American exomes (gnomAD v2.1.1). PP3 - REVEL = 0.81. PP4 - Variant meets PM2. Identified in at least 1 FH case with clinical diagnosis of definite heterozygous hypercholesterolemia by DLCN score from PMID 16250003. -
Uncertain significance, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Arg115Cys variant in LDLR has been reported in at least 5 individuals (including 1 Dutch individual) with Familial Hypercholesterolemia, segregated with disease in 5 affected relatives from 2 families (PMID: 16250003; Variation ID: 251162), and has been identified in 0.01446% (5/34586) of Latino chromosomes and 0.005446% (1/18362) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs774723292). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. This variant has also been reported as a VUS, likely pathogenic variant, and a pathogenic variant in ClinVar (Variation ID: 251162). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP1_Moderate, PP3, PS4_Supporting (Richards 2015). -

Familial hypercholesterolemia Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 03, 2023	This missense variant replaces arginine with cysteine at codon 115 of the LDLR protein. This variant is also known as p.Arg94Cys in the mature protein. This variant is located in the type A repeat 3 ligand binding domain (aa 107-145) 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). A functional study using a pig model has shown that this variant disrupts LDLR activity (PMID: 10064736). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 16250003, 30270359, 34074024, 33418990) in the literature, including three hypercholesterolemic individuals in one family (PMID: 30270359). This variant has also been reported in affected individuals by external laboratories (ClinVar submission SCV000583664.1, SCV000503143.1, SCV001482448.1). This variant has been identified in 7/250716 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	research	Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 13, 2022	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 115 of the LDLR protein (p.Arg115Cys). This variant is present in population databases (rs774723292, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of LDLR-related conditions (PMID: 16250003, 33418990). ClinVar contains an entry for this variant (Variation ID: 251162). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 08, 2023

Reported as likely pathogenic by the ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel in ClinVar (Accession: SCV001960959.1); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19544207, 10064736, 30270359, 30583242, 34906454, 33418990, 16250003) -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 05, 2024

The c.343C>T (p.R115C) alteration is located in exon 4 (coding exon 4) of the LDLR gene. This alteration results from a C to T substitution at nucleotide position 343, causing the arginine (R) at amino acid position 115 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D;.;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	M;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.8	D;D;D;D
Sift	Uncertain	0.023	D;D;D;D
Sift4G	Uncertain	0.019	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.50
MVP		1.0
MPC		0.94
ClinPred		0.88	D
GERP RS		5.3
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.58
gMVP		0.96

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

Other links and lift over

dbSNP: rs774723292; hg19: chr19-11215925; COSMIC: COSV52943323; COSMIC: COSV52943323;