rs747134711

Variant names:

• chr19-11120101-T-C
• rs747134711
• NM_000527.5:c.1855T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS3_Supporting PM2 PS4_Supporting PP3 PP4

This summary comes from the ClinGen Evidence Repository: 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)). LINK:https://erepo.genome.network/evrepo/ui/classification/CA037227/MONDO:0007750/013

• 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 Likely_pathogenic. Variant got 6 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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 rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1855T>C	p.Phe619Leu	missense_variant	Exon 13 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1855T>C	p.Phe619Leu	missense_variant	Exon 13 of 18	1	NM_000527.5	ENSP00000454071.1

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

Aug 28, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Aug 22, 2019

Robarts Research Institute, Western University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 16, 2016

Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 18, 2021

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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

Jan 13, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 12, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

not provided Pathogenic:1

Apr 03, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; Also known as p.F598L; This variant is associated with the following publications: (PMID: 17094996, 29720182, 9409298, 17539906, 20236128, 9544745) -

Cardiovascular phenotype Pathogenic:1

May 13, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1855T>C (p.F619L) alteration is located in exon 13 (coding exon 13) of the LDLR gene. This alteration results from a T to C substitution at nucleotide position 1855, causing the phenylalanine (F) at amino acid position 619 to be replaced by a leucine (L). Based on data from gnomAD, the C allele has an overall frequency of <0.001% (1/251492) total alleles studied. The highest observed frequency was 0.003% (1/30616) of South Asian alleles. 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, 1997; Sun, 1998; Taylor, 2007; Tosi, 2007; Paththinige, 2018; Pillai, 2022). This amino acid position is well conserved in available vertebrate species. Studies performed on cultured patient cells with this variant showed reduced LDLR expression and activity (Sun, 1997). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely 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
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.1	D;D;D;D;D;D
REVEL	Pathogenic	0.86
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;