19-11105408-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000527.5(LDLR):c.502G>C(p.Asp168His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,684 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. D168E) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 9.87

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 Pathogenic. Variant got 18 ACMG points.

PM1

In a disulfide_bond (size 17) in uniprot entity LDLR_HUMAN there are 50 pathogenic changes around while only 1 benign (98%) 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 chr19-11105410-C-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.996

PP5

Variant 19-11105408-G-C is Pathogenic according to our data. Variant chr19-11105408-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11105408-G-C is described in Lovd as [Pathogenic]. Variant chr19-11105408-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.502G>C	p.Asp168His	missense_variant	Exon 4 of 18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.502G>C	p.Asp168His	missense_variant	Exon 4 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461684

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727148

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.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:3

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

0/190 non-FH alleles -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided

Pathogenic:1

Feb 29, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LDLR c.502G>C (p.Asp168His) variant, also known as FH Sephardic, has been reported in the published literature in individuals and families with familial hypercholesterolemia (FH) (PMIDs: 8462973 (1993), 8882879 (1996), 16250003 (2005), 20828696 (2010), 28104544 (2017), 33418990 (2021)), as well as being described as a founder variant for FH within the Sephardic Jewish population (PMIDs: 8462973 (1993), 8882879 (1996)). This variant has shown to segregate with disease in one Sephardic Jewish family (PMID: 8462973 (1993)). Functional studies show this variant decreases normal LDL receptor transportation activity and antibody binding (PMID: 8462973 (1993)) in addition to impacting hydrogen bonding and amino acid residue acidity (PMID: 31401775 (2019)). Other variants impacting the p.168 residue have been seen in individuals with FH and are classified as pathogenic (PMIDs: 9259195 (1997), 9678702 (1998), 12124988 (2002), 15556094 (2004), 16205024 (2005), 15823276 (2005), 19007590 (2008), 20145306 (2008), 24529145 (2014)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Oct 05, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D168H pathogenic mutation (also known as c.502G>C), located in coding exon 4 of the LDLR gene, results from a G to C substitution at nucleotide position 502. The aspartic acid at codon 168 is replaced by histidine, an amino acid with similar properties. This mutation was first reported (as legacy p.D147H) in multiple families from a Sephardic Jewish hypercholesterolemia cohort, including one family with segregation in multiple affected heterozygous and homozygous cases; in vitro functional studies in homozygous fibroblasts demonstrated significant impact on LDLR trafficking and LDL binding (Leitersdorf E et al. Hum. Genet., 1993 Mar;91:141-7). This mutation has also been reported in additional familial hypercholesterolemia (FH) cohorts (Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; Medeiros AM et al. Atherosclerosis, 2010 Oct;212:553-8; Durst R et al. Atherosclerosis, 2017 02;257:55-63). In addition, alternate amino acid substitutions at this codon, p.D168Y, p.D168N, p.D168A, p.D168E, p.D168G, have also been reported in individuals with FH, indicating this position may be a hotspot location (Christiano AM et al. Am. J. Hum. Genet., 1996 Apr;58:671-81; Day IN et al. Hum. Mutat., 1997;10:116-27; Santos PC et al. Atherosclerosis, 2014 Mar;233:206-10; Sözen MM et al. Atherosclerosis, 2005 May;180:63-71; Chmara M et al. J. Appl. Genet., 2010;51:95-106). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Familial hypercholesterolemia

Pathogenic:1

Nov 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 168 of the LDLR protein (p.Asp168His). Experimental studies have shown that this missense change affects LDLR function (PMID: 8462973). This variant disrupts the p.Asp168 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9259195, 9678702, 12124988, 15556094, 16205024, 19007590). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. 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: 251258). This variant is also known as p.D147H and FH-Sephardic. This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 8462973, 16250003, 20828696, 28104544). It has also been observed to segregate with disease in related individuals. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.97

D;.;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

1.0

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.6

H;.;.;H

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-6.4

D;D;D;D

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.87

MutPred

0.95

Loss of disorder (P = 0.0457);Loss of disorder (P = 0.0457);.;Loss of disorder (P = 0.0457);

MVP

1.0

MPC

0.88

ClinPred

1.0

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

1.0

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over