chr19-11105495-T-G

Variant names:

• chr19-11105495-T-G
• rs730882085
• NM_000527.5:c.589T>G

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000527.5(LDLR):​c.589T>G​(p.Cys197Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. C197F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 5.82
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 15 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 chr19-11105496-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 251309.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 678 curated pathogenic missense variants (we use a threshold of 10). The gene has 92 curated benign missense variants. Gene score misZ: 0.12407 (below the threshold of 3.09). Trascript score misZ: 0.59338 (below the threshold of 3.09). GenCC associations: The gene is linked to hypercholesterolemia, familial, 1, homozygous familial hypercholesterolemia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 19-11105495-T-G is Pathogenic according to our data. Variant chr19-11105495-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 251308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.589T>G	p.Cys197Gly	missense_variant	Exon 4 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.589T>G	p.Cys197Gly	missense_variant	Exon 4 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4

-

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

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: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

subject mutated among 2600 FH index cases screened = 1, family member=1 / Software predictions: Damaging -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Mar 18, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PM1, PM2, PM5, PP3 -

not provided Pathogenic:2

Feb 10, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID#251308; ClinVar); Not observed at significant frequency in large population cohorts (gnomAD); Also denoted as C176G due to alternate nomenclature; This variant is associated with the following publications: (PMID: 31447099, 28964736, 32143996, 20809525, 34037665, 26582918, 24014831, 27535533, 2988123, 12459547, 9026534, 1301956, 18096825, 20538126, 21276076, 23064986, 27765764, 27816806, 30293936, 33740630, 33994402) -

Sep 09, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Other pathogenic or likely pathogenic variants affect the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function. -

Familial hypercholesterolemia Pathogenic:2

Aug 21, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pathogenic variant based on current evidence: This missense variant (also known as p.Cys176Gly in the mature protein) is located in the fifth LDLR type A repeat of the ligand binding domain of the LDLR protein. This variant changes one of the functionally critical cysteine residues that form intra-repeat disulfide bonds in the ligand binding domain (PMID: 15952897) and is expected to have deleterious impact on the LDLR protein folding and stability. Experimental functional study has shown no detectable LDLR activity in cells from an individual compound heterozygous for this variant and deletion of exons 4-18 (PMID: 24014831). Computational splicing tools suggest that this variant may not impact the RNA splicing. While this variant is rare in the general population (0/277264 chromosomes in the Genome Aggregation Database), it has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 20809525, 24014831, 28964736). In addition, different variants occurring in the same amino acid position (p.Cys197Arg, p.Cys197Phe and p.Cys197Tyr) are considered deleterious (Clinvar). Based on available evidence, this variant is classified as Pathogenic. -

Mar 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 197 of the LDLR protein (p.Cys197Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 20809525, 24014831). ClinVar contains an entry for this variant (Variation ID: 251308). 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%. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). This variant disrupts the p.Cys197 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 1301956, 18096825, 20145306, 20538126, 20809525, 21276076, 23064986, 24014831, 27765764, 27816806), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Homozygous familial hypercholesterolemia Pathogenic:1

Jul 18, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Cys197Gly variant in LDLR has been reported in at least 3 individuals wit h hypercholesterolemia (FH), one of which was compound heterozygous (with a dele tion of exons 4-18) and had homozygous familial hypercholesterolemia (Marduel 2 010, Stein 2013, Defesche 2017, ClinVar: Variation ID 251308). This variant was absent from large population studies. Functional studies provide some evidence that the p.Cys197Gly variant may impact protein function (Stein 2013). However, these types of assays may not accurately represent biological function. Computat ional prediction tools and conservation analysis suggest that the p.Cys197Gly va riant may impact the protein, though this information is not predictive enough t o determine pathogenicity. Finally, other variants at this position (Cys197Arg, Cys197Tyr, Cys197Phe, Cys197Trp) have been reported in individuals with FH (Clin var, HGMD database), suggesting that changes at this position are not tolerated. In summary, although additional studies are required to fully establish its cli nical significance, the p.Cys197Gly variant is likely pathogenic. ACMG/AMP Crite ria applied: PM2; PM3; PP3; PS3_Supporting; PS4_Supporting. -

Cardiovascular phenotype Pathogenic:1

Jan 29, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C197G pathogenic mutation (also known as c.589T>G), located in coding exon 4 of the LDLR gene, results from a T to G substitution at nucleotide position 589. The cysteine at codon 197, located in LDLR class A repeat 5, is replaced by glycine, an amino acid with highly dissimilar properties. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). This alteration has been reported in individuals with FH (Marduel M et al. Hum. Mutat., 2010 Nov;31:E1811-24; Stein EA et al. Circulation, 2013 Nov;128:2113-20; Defesche JC et al. J Clin Lipidol Sep;11:1338-1346.e7). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 5. In addition, alterations affecting the same amino acid (C197Y, C197W, C197F, C197R) have also been described in FH (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Chmara M et al. J Appl Genet. 2010;51(1):95-106; Webb JC et al. J. Lipid Res., 1996 Feb;37:368-81). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.96	D;.;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.65	T;T;T;T
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.5	H;.;.;H
PhyloP100		5.8
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-9.3	D;D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		0.93	P;.;.;.
Vest4		0.90
MutPred		0.96		Loss of catalytic residue at P196 (P = 0.0064);Loss of catalytic residue at P196 (P = 0.0064);.;Loss of catalytic residue at P196 (P = 0.0064);
MVP		1.0
MPC		0.91
ClinPred		1.0	D
GERP RS		5.6
PromoterAI		-0.0031	Neutral
Varity_R		0.99
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs730882085; hg19: chr19-11216171;