rs747134711

chr19-11120101-T-C

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.1855T>C(p.Phe619Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,856 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. F619C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:9 U:2
• Conservation: PhyloP100: 7.85

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 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 10 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 chr19-11120102-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 252085.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 19-11120101-T-C is Pathogenic according to our data. Variant chr19-11120101-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 252083.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-11120101-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.1855T>C	p.Phe619Leu	missense_variant	13/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.1855T>C	p.Phe619Leu	missense_variant	13/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251492 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461856 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000111 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:9 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Aug 22, 2019	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
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	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 28, 2023	This missense variant (also known as p.Phe598Leu in the mature protein) replaces phenylalanine with leucine at codon 619 in the LDLR type B repeat 6 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). Functional studies using lymphocytes from a heterozygous individual affected with familial hypercholesterolemia have shown that this variant causes a 60-65% residual level of LDLR activity and expression (PMID: 9409298). This variant has been reported in several heterozygous individuals affected with familial hypercholesterolemia (PMID: 9409298, 17094996, 17539906, 20236128, 29720182, 34998859; Color internal data; ClinVar SCV000484688.2, SCV000503426.1, SCV001960933.1). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in an individual affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 34998859). This variant has been identified in 1/251492 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, p.Phe619Ser and p.Phe619Cys, are considered to be disease-causing (ClinVar variation ID: 252084 and 252085), suggesting that phenylalanine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 18, 2021	NM_000527.5(LDLR):c.1855T>C (p.Phe619Leu) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS3_Supporting, PS4_Supporting) 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: PM2 - PopMax MAF = 0.00003266 (0.003266%) in East Asian (gnomAD v2.1.1). PP3 - REVEL: 0,857. PP4 - Variant meets PM2. Variant identified in 2 index cases fulfilling validated clinical criteria for FH from different labs. PS3_supporting - PMID: 9409298 - Level 3 assay - study on htz patient's cultured lymphoblasts, immunoblotting + I125-LDL assay, no precursor detectable, degradation of 125I-LDL 63%. ---- functional study is consistent with damaging effect. PS4_supporting - Variant meets PM2. Variant identified in 2 index cases (1 case with Simon-Broome from Color laboratory; 1 case with DLCN criteria from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA)). -

Familial hypercholesterolemia Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 15, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Phe619 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20809525). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 252083). This variant is also known as Phe598Leu. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9544745, 17539906; Invitae). This variant is present in population databases (rs747134711, gnomAD 0.003%). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 619 of the LDLR protein (p.Phe619Leu). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 13, 2022	Variant summary: LDLR c.1855T>C (p.Phe619Leu) 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 4e-06 in 251492 control chromosomes. c.1855T>C has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Sun_1997, Tosi_2007, Taylor_2007, Paththinige_2018). Additionally, experimental studies performed on a heterozygous patient's cultured lymphoblasts showed LDL-receptor expression and activity was reduced to around 60% of wild-type, consistent with damaging effect of the variant (Sun_1997). The variant was classified as likely pathogenic by ClinGen Familial Hypercholesterolemia Expert Panel for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS3_Supporting, PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as VUS (3) and likley pathogenic (1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 12, 2023	This missense variant (also known as p.Phe598Leu in the mature protein) replaces phenylalanine with leucine at codon 619 in the LDLR type B repeat 6 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). Functional studies using lymphocytes from a heterozygous individual affected with familial hypercholesterolemia have shown that this variant causes a 60-65% residual level of LDLR activity and expression (PMID: 9409298). This variant has been reported in several heterozygous individuals affected with familial hypercholesterolemia (PMID: 9409298, 17094996, 17539906, 20236128, 29720182, 34998859; Color internal data; ClinVar SCV000484688.2, SCV000503426.1, SCV001960933.1). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in an individual affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 34998859). This variant has been identified in 1/251492 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, p.Phe619Ser and p.Phe619Cys, are considered to be disease-causing (ClinVar variation ID: 252084 and 252085), suggesting that phenylalanine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 27, 2022

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies using a heterozygous patient's cultured lymphoblasts reveal reduced LDL receptor activity (Sun et al., 1997); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as likely pathogenic by the ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel; Also known as p.F598L; This variant is associated with the following publications: (PMID: 17094996, 29720182, 9409298, 17539906, 20236128, 9544745) -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 15, 2024

The p.F619L variant (also known as c.1855T>C), located in coding exon 13 of the LDLR gene, results from a T to C substitution at nucleotide position 1855. The phenylalanine at codon 619 is replaced by leucine, an amino acid with highly similar properties. This variant (also referred to as p.F598L) has been detected in probands reported to have familial hypercholesterolemia (FH), and co-occurred with a second LDLR variant in an individual with features consistent with homozygous FH (Sun XM et al. Arterioscler Thromb Vasc Biol, 1997 Nov;17:3092-101;Sun XM et al. Atherosclerosis, 1998 Jan;136:175-85; Tosi I et al. Atherosclerosis, 2007 Sep;194:102-11;Taylor A et al. Clin Genet, 2007 Jun;71:561-8;Paththinige CS et al. Lipids Health Dis, 2018 May;17:100; Pillai KKB et al. Clin Chim Acta, 2022 Feb;527:47-55). Studies performed on cultured patient cells with this variant showed reduced LDL-R expression and activity (Sun XM et al. Arterioscler Thromb Vasc Biol, 1997 Nov;17:3092-101). This amino acid position is well 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;.;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;.;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.1	D;D;D;D;D;D
Sift	Uncertain	0.0030	D;D;D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D;D
Polyphen		0.40	B;.;.;.;.;.
Vest4		0.64
MutPred		0.97		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);.;.;.;Gain of sheet (P = 0.0477);
MVP		1.0
MPC		0.78
ClinPred		0.97	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.99

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

Other links and lift over

dbSNP: rs747134711; hg19: chr19-11230777;