rs746959386

Positions:

• chr19-11116209-C-G
• chr19-11116209-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000527.5(LDLR):​c.1702C>G​(p.Leu568Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000345 in 1,449,190 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. L568P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 4.00

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 18 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 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 chr19-11116210-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 19-11116209-C-G is Pathogenic according to our data. Variant chr19-11116209-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11116209-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.1702C>G	p.Leu568Val	missense_variant	11/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.1702C>G	p.Leu568Val	missense_variant	11/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1449190 Hom.: 0 Cov.: 27 AF XY: 0.00000277 AC XY: 2 AN XY: 721862

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.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:5

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	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Pathogenic, criteria provided, single submitter	curation;literature only	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Familial hypercholesterolemia Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 31, 2020	This missense variant (also known as p.Leu547Val in the mature protein) replaces leucine with valine at codon 568 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Computational splicing tools suggest that this variant may impact RNA splicing by activating a new splice donor site. This splice prediction has not been investigated in published RNA studies. It has been shown that this variant segregates with disease in 3 related individuals from a family affected with familial hypercholesterolemia (PMID: 26510755). This variant has been reported in multiple Japanese individuals affected with familial hypercholesterolemia (PMID: 10447263, 18718593, 26632531, 31491741) and is thought to occur at 3.4% of affected individuals, compared to 0.08% minor allele frequency in the general population in Japan (PMID: 18718593). This variant has also been identified in a Korean individual affected with familial hypercholesterolemia (PMID: 26343872). Carriers of this variant show very mild clinical phenotype due to ~75% residual LDL binding activity of the mutant protein (PMID: 18718593). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2022	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 568 of the LDLR protein (p.Leu568Val). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu568 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 20809525), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 251976). This variant is also known as p.L547V. This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 10447263, 18718593, 25962062, 26510755). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 11, 2024	Variant summary: LDLR c.1702C>G (p.Leu568Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251292 control chromosomes. c.1702C>G has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia and homozygous or compound heterozygous individuals show more severe and early onset of disease (Miyake_2009, Miyagi_2016, Tada_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed mild effect of this variant on LDLR-mediated LDL-binding in patient's fibroblasts in an in vitro assay (76% of wt in homozygous state and 92% of wt in heterozygous state), consistent with relative mild phenotype in homozygous or heterozygous individuals with this variant (Muyake_2018). The following publications have been ascertained in the context of this evaluation (PMID: 31491741, 26510755, 18718593, 30241732). ClinVar contains an entry for this variant (Variation ID: 251976). Based on the evidence outlined above, the variant was classified as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2022

The p.L568V variant (also known as c.1702C>G), located in coding exon 11 of the LDLR gene, results from a C to G substitution at nucleotide position 1702. The leucine at codon 568 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported as a heterozygote and compound heterozygote in familial hypercholesterolemia (FH) cohorts and has been reported in multiple family members in an affected family (Hattori H et al. Hum Mutat, 1999;14:87; Ohshiro T et al. J Atheroscler Thromb, 2010 Oct;17:1113; Miyagi Y et al. J Atheroscler Thromb, 2016 Oct;23:112-7; Sturm AC et al. JAMA Cardiol, 2021 08;6:902-909; Nagahara K et al. J Atheroscler Thromb, 2021 May). This variant is also considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.;.;.;.;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	1.5	L;.;.;.;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D
Polyphen		0.97	D;.;.;.;.;.
Vest4		0.56
MutPred		0.89		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;.;.;Gain of sheet (P = 0.0827);
MVP		1.0
MPC		0.80
ClinPred		0.96	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.59
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.23		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs746959386; hg19: chr19-11226885;