rs201102461

chr19-11105250-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1 PM2 PM5 BP4_Strong

The NM_000527.5(LDLR):c.344G>A(p.Arg115His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000824 in 1,613,420 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R115C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000082 (1 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:4 U:7 B:2
• Conservation: PhyloP100: 1.24

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 Uncertain_significance. Variant got 2 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 chr19-11105249-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251162.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.062245935).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.344G>A	p.Arg115His	missense_variant	4/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.344G>A	p.Arg115His	missense_variant	4/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152118 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000180 AC: 45 AN: 250682 Hom.: 0 AF XY: 0.000192 AC XY: 26 AN XY: 135724

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00223

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000821 AC: 120 AN: 1461184 Hom.: 1 Cov.: 33 AF XY: 0.0000812 AC XY: 59 AN XY: 726902

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00280

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74432

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00000579 Hom.: 0

Bravo AF: 0.0000642

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000189 AC: 23

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:4 Uncertain:7 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4 Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 04, 2021	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 07, 2021	The NM_000527.5(LDLR):c.344G>A (p.Arg115His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PS3) 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: PS3 - Level 1 assays: PMID 12837857: Heterologous cells (COS-7), FACS assays - results - 64% LDLR expression and activity ---- results are below 70% of wild-type, so PS3 is Met. -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	curation;literature only	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -
Likely benign, 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, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 01, 2017	The LDLR c.344G>A (p.Arg115His) missense variant has been reported in five studies and is found in a total of eight individuals with hypercholesterolemia, including one individual who carried the variant in a compound heterozygous state with a stop-gained variant and seven individuals who carried the variant in a heterozygous state (Khoo et al. 2000; Yu et al. 2002; Kim et al. 2004; Chiou et al. 2011; Mabuchi et al. 2011). Control data are unavailable for this variant, which is reported at a frequency of 0.00234 in the East Asian population of the Genome Aggregation Database. Based on the evidence, the p.Arg115His variant is classified as likely pathogenic for familial hypercholesterolemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Familial hypercholesterolemia Uncertain:2 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 21, 2021	This sequence change replaces arginine with histidine at codon 115 of the LDLR protein (p.Arg115His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs201102461, ExAC 0.2%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 9399845, 11005141, 12417285, 15359125, 18718593, 28502495, 28932795, 29399563). This variant is also known as R94H. ClinVar contains an entry for this variant (Variation ID: 225402). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LDLR function (PMID: 12837857, 27821657). 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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 01, 2021	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 17, 2021

Identified in multiple individuals with familial hypercholesterolemia (FH); however, the variant did not segregate with disease in at least two families (Maruyama et al., 2004; Miyake et al., 2009; Kim et al., 2018; Hori et al., 2019; Hori et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate a damaging effect: reduced protein expression and receptor activity (Chang et al., 2003); Also known as p.R94H or FH-Fukuoka; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#225402; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 12417285, 21146822, 9399845, 21376320, 11005141, 20538126, 15359125, 15256764, 20599862, 18718593, 12837857, 32331935, 27821657, 30827231, 31491741, 32719484, 29399563, 28932795, 28502495, 29192238, 32252761) -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2024

The p.R115H variant (also known as c.344G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 344. The arginine at codon 115 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in multiple East Asian familial hypercholesterolemia cohorts (Khoo KL et al. Clin. Genet. 2000;58:98-105; Yu W et al. Atherosclerosis. 2002;165:335-42; Kim JH et al. Mol. Cells. 2004;18:63-70; Chiou KR et al. Am. J. Cardiol. 2010;105:1752-8; Kim HN et al. Chonnam Med J. 2018;54:31-35; Tada H et al. J Clin Lipidol. 2018:397-402.e2). One functional study suggested this alteration leads to an approximately 35% reduction in both the amount of mature LDLR protein and LDLR activity compared to wildtype; however, the physiological relevance of this decrease is unclear (Chang JH et al. J. Lipid Res. 2003;44:1850-8). Based on data from gnomAD, the A allele has an overall frequency of approximately 0.02% (48/276574) total alleles studied. The highest observed frequency was 0.23% (44/18844) of East Asian alleles. Based on data from the 2KJPN database, the population frequency in Japan is 0.39% (Yamaguchi-Kabata Y et al. J. Hum. Genet. 2018;63:213-230). This amino acid position is highly conserved through mammals but not in all 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	0.098
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Pathogenic	0.14
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D;.;.;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T;T;T;T
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.062	T;T;T;T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	1.4	L;.;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.8	N;N;N;N
Sift	Benign	0.069	T;T;T;T
Sift4G	Benign	0.12	T;T;T;T
Polyphen		0.16	B;.;.;.
Vest4		0.26
MVP		1.0
MPC		0.37
ClinPred		0.029	T
GERP RS		4.3
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.21
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs201102461; hg19: chr19-11215926;