chr19-11116892-C-T

Position:

chr19-11116892-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS3_SupportingPM2PP3PP4PP1PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1739C>T (p.Ser580Phe) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP1, PP3, PP4, PS3_Supporting and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). PP3: REVEL=0.907. PS3_Supporting: Level 3 assay: PMID 35474963 (Pfisterer SG et al., 2022): Heterozygous patient monocytes and lymphocytes. 25-50% of control low-density lipoprotein particle uptake and LDLR surface expression. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 3 unrelated index cases who fulfill DLCN score >=6 (1 case from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 2 cases from Research Lab of Molecular Genetics of Lipid Metabolism, Italy - Prof. M. Arca). PP1: Variant segregates with FH phenotype in 2 informative meioses identified by Research Lab of Molecular Genetics of Lipid Metabolism, Italy - Prof. M. Arca. 1 affected family member has the variant and 1 unaffected family member does not have the variant. LINK:https://erepo.genome.network/evrepo/ui/classification/CA305301758/MONDO:0007750/013

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

13

5

1

Clinical Significance

Likely pathogenic reviewed by expert panel P:6

Conservation

PhyloP100: 7.79

Variant links:

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]

LDLR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 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.

PP1

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/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.1739C>T	p.Ser580Phe	missense_variant	12/18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.1739C>T	p.Ser580Phe	missense_variant	12/18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

Cov.:

32

GnomAD3 exomes

AF:

0.00000398

AC:

1

AN:

251488

Hom.:

0

AF XY:

0.00000736

AC XY:

1

AN XY:

135918

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

1

AN:

1461808

Hom.:

0

Cov.:

35

AF XY:

0.00000138

AC XY:

1

AN XY:

727204

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

32

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	May 24, 2021	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Nov 07, 2023	The NM_000527.5(LDLR):c.1739C>T (p.Ser580Phe) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP1, PP3, PP4, PS3_Supporting and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). PP3: REVEL=0.907. PS3_Supporting: Level 3 assay: PMID 35474963 (Pfisterer SG et al., 2022): Heterozygous patient monocytes and lymphocytes. 25-50% of control low-density lipoprotein particle uptake and LDLR surface expression. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 3 unrelated index cases who fulfill DLCN score >=6 (1 case from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 2 cases from Research Lab of Molecular Genetics of Lipid Metabolism, Italy - Prof. M. Arca). PP1: Variant segregates with FH phenotype in 2 informative meioses identified by Research Lab of Molecular Genetics of Lipid Metabolism, Italy - Prof. M. Arca. 1 affected family member has the variant and 1 unaffected family member does not have the variant. -
Likely pathogenic, criteria provided, single submitter	curation;literature only	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -

Familial hypercholesterolemia

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 580 of the LDLR protein (p.Ser580Phe). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of autosomal dominant and autosomal recessive familial hypercholesterolemia (PMID: 21865347, 31947532, 32977124; Invitae). ClinVar contains an entry for this variant (Variation ID: 438325). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 07, 2022	This missense variant (also known as p.Ser559Phe in the mature protein) replaces serine with phenylalanine at codon 580 in the LDLR type B repeat 5 in the EGF precursor homology domain 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). This variant has been reported in nine unrelated individuals affected with familial hypercholesterolemia (PMID: 21865347, 34297352, Schoen et al. 2014 doi:10.1016/j.jacl.2014.02.029). This variant has also been observed in the compound heterozygous state with other pathogenic LDLR variants (p.Gly549Asp, p.Gly592Glu) in two unrelated individuals affected with homozygous familial hypercholesterolemia (PMID: 21865347, 31947532). Reduced LDL uptake activities were observed in leukocytes from two of the affected carriers (PMID: 21865347, 35474963). This variant has been identified in 1/251488 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 02, 2022

The p.S580F variant (also known as c.1739C>T), located in coding exon 12 of the LDLR gene, results from a C to T substitution at nucleotide position 1739. The serine at codon 580 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration is located immediately adjacent to the YWTD motif in the LDLR class B repeat 5. This variant has been previously reported in both the heterozygous and compound heterozygous states (with LDLR p.G549D and p.G592E mutations) in individuals reported to have a clinical diagnosis of familial hypercholesterolemia (Romano M et al. J. Lipid Res. 2011;52:2095-100; Di Taranto MD et al. J Clin Med. 2020 Jan;9(1); Di Taranto MD et al. Clin Genet. 2021 11;100(5):529-541). LDLR activity was reduced in lymphocytes derived from both heterozygous and a compound heterozygous individuals, with cells from the heterozygous patient exhibiting ~65% of the LDLR activity in control cells and cells from a compound heterozygote displaying 30-40% of control LDLR activity (Romano M et al. J. Lipid Res. 2011;52:2095-100). Internal structural analysis predicts that this variant results in a significant decrease in structural stability (Jeon H et al. Nat Struct Biol. 2001 Jun;8(6):499-504; Ambry internal data). This amino acid position is highly 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

0.94

BayesDel_addAF

Pathogenic

0.55

D

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

28

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

D;.;.;.;.;.

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.99

D

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D

M_CAP

Pathogenic

0.71

D

MetaRNN

Pathogenic

0.96

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Uncertain

2.7

M;.;.;.;.;M

PrimateAI

Uncertain

0.66

T

PROVEAN

Pathogenic

-5.8

D;D;D;D;D;D

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.85

MutPred

0.76

Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);.;.;.;Gain of sheet (P = 0.0149);

MVP

1.0

MPC

0.85

ClinPred

0.99

D

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.98

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs934496989; hg19: chr19-11227568;