rs121908026

Positions:

• chr19-11105436-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 20P and 4B. BS4 PM2 PM1 PM3 PP3 PP4 PS3 PS4 PP1_Strong

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR): c.530C>T (p.Ser177Leu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS3, PS4, PM1, PM2, PM3, PP1_Strong, PP3, PP4 and BS4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PS3 - PMID:31578082 - Level 1 assay - Heterologous cells (CHO), FACS assays and CLSM: 65% cell surface LDLR, 10% binding and <2% uptake. PMID:2760205 - Level 2 assay - Homozygous patient fibroblast, 125I-LDL assays: <2% LDLR activity. PMID:25647241 - Level 3 assay - Heterologous cells (HeLa), CLSM assays: LDLR activity decreased compared to WT - considered as disruptive.PS4 - Variant meets PM2. Variant identified in 30 unrelated index cases (5 cases (2 with DLCN≥6; 3 with Simon-Broome possible) from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 1 case with Simon-Broome possible from GeneDx Inc.; 11 cases with Simon-Broome possible from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; 13 cases with Simon-Broome possible/definite from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation).PM1 - Variant meets PM2 and is missense in exon 4.PM2 - PopMax MAF = 0.00006533 (0.006533%) in South Asian exomes+genomes (gnomAD v2.1.1).PM3 - Patient 3 from PMID:18263977 has LDL = 19.7 mmol/l and also LDLR p.Arg350* in trans - Pathogenic by these guidelines. Two true homozygotes (FHF23 and FHF57) published in PMID:27816806 had LDL = 16.2 mmol/l and 22.6 mmol/l, respectively.PP1_Strong - Variant segregates with FH phenotype in 52 informative meiosis in 26 families from different labs (Laboratory of Genetics and Molecular Cardiology, University of São Paulo; Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge): 43 relatives tested positive had LDL-C >75th percentile + 9 relatives tested negative had LDL-C <50th percentile.PP3 - REVEL = 0.886.PP4 - Variant meets PM2. Variant identified in 30 unrelated index cases who fulfill clinical criteria for FH from several labs (see PS4 for details).BS4 - Variant does not segregate with phenotype in 14 informative meiosis from at least 6 families from different labs (Laboratory of Genetics and Molecular Cardiology, University of São Paulo; Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge): 13 relatives tested negative but had LDL-C >75th percentile + 1 relative tested positive but LDL-C <50th percentile.Variant has 3 Strong, 3 Moderate and 2 Supporting evidence codes towards Pathogenic, enough to classify as Pathogenic, and only 1 Strong evidence codes towards Benign. The Pathogenic criteria overwhelms the Benign criteria, so we are confident in classifying this variant as Pathogenic. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023715/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.000039 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:25 O:1
• Conservation: PhyloP100: 4.87

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 16 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.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: 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.
• BS4: 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	c.530C>T	p.Ser177Leu	missense_variant	4/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.530C>T	p.Ser177Leu	missense_variant	4/18	1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152202 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251308 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135880

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461728 Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7 AN XY: 727172

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152202 Hom.: 1 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74344

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000956

Bravo AF: 0.0000529

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:25 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:16

Pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 1993	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	- -
Pathogenic, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/190 non-FH alleles, 0/32 normolipidemic individuals; 0/60 healthy control individuals -
Pathogenic, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 03, 2022	NM_000527.5(LDLR): c.530C>T (p.Ser177Leu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS3, PS4, PM1, PM2, PM3, PP1_Strong, PP3, PP4 and BS4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS3 - PMID: 31578082 - Level 1 assay - Heterologous cells (CHO), FACS assays and CLSM: 65% cell surface LDLR, 10% binding and <2% uptake. PMID: 2760205 - Level 2 assay - Homozygous patient fibroblast, 125I-LDL assays: <2% LDLR activity. PMID: 25647241 - Level 3 assay - Heterologous cells (HeLa), CLSM assays: LDLR activity decreased compared to WT - considered as disruptive. PS4 - Variant meets PM2. Variant identified in 30 unrelated index cases (5 cases (2 with DLCN≥6; 3 with Simon-Broome possible) from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 1 case with Simon-Broome possible from GeneDx Inc.; 11 cases with Simon-Broome possible from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; 13 cases with Simon-Broome possible/definite from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation). PM1 - Variant meets PM2 and is missense in exon 4. PM2 - PopMax MAF = 0.00006533 (0.006533%) in South Asian exomes+genomes (gnomAD v2.1.1). PM3 - Patient 3 from PMID: 18263977 has LDL = 19.7 mmol/l and also LDLR p.Arg350* in trans - Pathogenic by these guidelines. Two true homozygotes (FHF23 and FHF57) published in PMID: 27816806 had LDL = 16.2 mmol/l and 22.6 mmol/l, respectively. PP1_Strong - Variant segregates with FH phenotype in 52 informative meiosis in 26 families from different labs (Laboratory of Genetics and Molecular Cardiology, University of São Paulo; Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge): 43 relatives tested positive had LDL-C >75th percentile + 9 relatives tested negative had LDL-C <50th percentile. PP3 - REVEL = 0.886. PP4 - Variant meets PM2. Variant identified in 30 unrelated index cases who fulfill clinical criteria for FH from several labs (see PS4 for details). BS4 - Variant does not segregate with phenotype in 14 informative meiosis from at least 6 families from different labs (Laboratory of Genetics and Molecular Cardiology, University of São Paulo; Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge): 13 relatives tested negative but had LDL-C >75th percentile + 1 relative tested positive but LDL-C <50th percentile. Variant has 3 Strong, 3 Moderate and 2 Supporting evidence codes towards Pathogenic, enough to classify as Pathogenic, and only 1 Strong evidence codes towards Benign. The Pathogenic criteria overwhelms the Benign criteria, so we are confident in classifying this variant as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 08, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 13, 2023	The p.Ser177Leu variant in LDLR (also described as p.Ser156Leu in the literature) has been reported in several individuals with familial hypercholesterolemia (FH): In at least 15 in the heterozygous state (Schuster 1993 PMID: 8096412, Kuhrova 2002 PMID: 11754108, Bourbon 2008 PMID: 17765246, Tichy 2012 PMID: 22698793, Jannes 2015 PMID: 25461735, Thormaehlen 2015 PMID: 25647241, Sharifi 2016 PMID: 26892515), 1 with homozygous FH (Hobbs 1989 PMID: 2760205), and 2 in the compound heterozygous state (Jannes 2015 PMID: 25461735, Kubalska 2008 PMID: 18263977) and has also been reported by other clinical laboratories in ClinVar (Variation ID 3686). This variant segregated with disease in at least 9 affected relatives from 2 families (Hobbs 1992 PMID: 1301956, Schuster 1993 PMID: 8096412). However, not all family members that carried the variant presented with high cholesterol levels (Hobbs 1989 PMID: 2760205). This variant has also been identified in in 0.02% (3/15272) of Latino/Admixed American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1.2). This frequency is low enough to be consistent with the frequency of FH in the general population. In vitro functional studies provide some evidence that the p.Ser177Leu variant may impact protein function (Hobbs 1989 PMID: 2760205, Kubalska 2008 PMID: 18263977, Thormaehlen 2015 PMID: 25647241) and computational prediction tools and conservation analysis are consistent with pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. The ACMG/AMP Criteria applied: PS4, PP1_strong, PS3_supporting, PP3, PM2_Supporting. -
Likely pathogenic, 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	subjects mutated among 2600 FH index cases screened = 2 , family members = 3 with co-segregationFH-Puerto-Rico, 2% LDLR Activity / Software predictions: Damaging -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	The c.530C>T (p.Ser177Leu) variant, also known as p.Ser156Leu in the LDLR gene, that encodes for low density lipoprotein receptor, has been identified in heterozygous, compound heterozygous or homozygous state in numerous individuals (>30) who fulfill the clinical criteria of familial hypercholesterolemia (FH) and segregated with disease in multiple families (PMID: 8096412, 15241806, 17765246, 18263977, 22698793, 25461735, 25487149, 25647241, 2760205, 31578082, 27816806, 28235710, 9654205, 20145306). This variant has been reported in compound heterozygosity with a truncating variant (p.Arg350*) which is classified as pathogenic by the ClinGen Variant Curation Expert Panel (ClinVar ID:226342), in an individual with severe FH (LDL-C: 19.7mmol/l) (PMID: 18263977). Experimental studies using transfected LDLR-deficient CHO cells (CHO-ldlA7), true homozygous patient fibroblasts and transfected HeLa-Kyoto cells revealed that this variant causes significantly reduced LDLR expression, LDL binding and internalization (PMID: 31578082, 2760205, 25647241). This variant lies in the well-established LDL binding domain (amino acids 105-232) critical for protein function (PMID: 2600087). In-silico computational prediction tools suggest that the p.Ser177Leu variant may have deleterious effect on the protein function (REVEL score: 0.886). This variant is found to be rare (4/251308; 0.001592%) in the gnomAD database. This variant is reported in ClinVar as pathogenic (ID: 3686) by multiple submitters (23) and reviewed by the expert panel. Therefore, the c.530C>T (p.Ser177Leu) variant in the LDLR gene is classified as pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham	Jan 01, 2023	This missense change has been observed in individuals with familial hypercholesterolemia -

Familial hypercholesterolemia Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Aug 10, 2018	This c.530C>T (p.Ser177Leu) variant in exon 4 of the LDLR gene results in an amino acid change at residue 177 of a serine to a leucine. This variant has been reported in multiple patients and families with familial hypercholesterolemia (PMID: 8096412, 9654205, 15199436, 15241806, 17765246, 22698793, 25487149) and is rarely observed in general population databases. Functional assays have also shown that this variant is disruptive (PMID: 25647241). Therefore, the c.530C>T (p.Ser177Leu) variant in the LDLR gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 01, 2023	This missense variant (also known as p.Ser156Leu in the mature protein and as FH Puerto Rico) replaces serine with leucine at codon 177 in the LDLR type A repeat 4 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). Experimental functional studies have shown that this variant causes a significant reduction in LDLR expression, binding, and uptake (PMID: 2760205, 25647241, 31578082). This LDLR variant has been reported in over 30 heterozygous individuals affected with familial hypercholesterolemia (PMID: 2760205, 15241806, 17765246, 22698793, 25647241, 2760205, 28235710, 30975109, 31578082, 34037665; Color internal data). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant as well as in homozygosity in multiple individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 18263977, 25461735, 2760205, 27816806). It has been shown that this variant segregates with disease in over 15 affected individuals across 2 large families (PMID: 2760205, 30975109). This variant has been identified in 4/251308 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 21, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 177 of the LDLR protein (p.Ser177Leu). This variant is present in population databases (rs121908026, gnomAD 0.006%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 2760205, 15241806, 17765246, 22698793, 25487149, 25647241). ClinVar contains an entry for this variant (Variation ID: 3686). 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%. Experimental studies have shown that this missense change affects LDLR function (PMID: 2760205, 25647241). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 19, 2016	Variant summary: The LDLR c.530C>T (p.Ser177Leu) variant involves the alteration of a conserved nucleotide. Ser177 is a highly conserved amino acid across species, and 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/121078 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). This variant has been reported in numerous patients heterozygously or homozygously. Functional studies showed this variant with defective maturation and LDL metabolism. Taken together, this variant is classified as pathogenic. -

not provided Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 03, 2019	PS3_moderate, PS4_moderate, PM1, PM2, PM3, PP1, PP3 -
not provided, no classification provided	in vitro	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 09, 2022	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate defective receptor transport and ligand binding (Hobbs et al., 1989; Hobbs et al., 1992; Li et al., 2004; Thormaehlen et al., 2015); Disrupts a negatively charged triplet, Ser-Asp-Glu, located at the carboxyl-terminal end of the LDL-receptor class A4 repeat domain that is critical for ligand binding (Schneider et al., 2003); This variant is associated with the following publications: (PMID: 25647241, 15199436, 25487149, 30592178, 31491741, 30512145, 30975109, 8096412, 8828982, 14512370, 2760205, 1301956, 9654205, 14508510, 7947594, 14993243, 15241806, 15556092, 15556093, 16627557, 17335829, 17539906, 17765246, 18263977, 18279815, 19026292, 20145306, 21310417, 22698793, 25461735, 26892515, 27816806, 31447099, 32041611, 32660911, 32331935, 33740630, 34037665) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 05, 2022	The frequency of this variant in the general population, 0.000065 (2/30616 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in in individuals/families with familial hypercholesterolemia (PMIDs: 30592178 (2019), 22698793 (2012), 20145306 (2010), 17765246 (2008), 15241806 (2004), 9654205 (1998), 8096412 (1993), and 2760205 (1989)) as well as individuals who were homozygous or compound heterozygous with a second pathogenic LDLR variant (PMIDs: 27816806 (2016), 18263977 (2008), 9654205 (1998), and 2760205 (1989)). In addition, experimental studies have determined this variant results in reduced LDL binding (PMIDs: 25647241 (2015) and 1301956 (1992)). Based on the available information, this variant is classified as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2024

The p.S177L pathogenic mutation (also known as c.530C>T), located in coding exon 4 of the LDLR gene, results from a C to T substitution at nucleotide position 530. The serine at codon 177 is replaced by leucine, an amino acid with dissimilar properties. This alteration impacts a residue in the conserved cluster of acidic amino acids at the C-terminal end of LDLR class A repeat 4 (Jeon H and Blacklow C. Annu. Rev. Biochem. 2005;74:535-62). This variant (also described as legacy p.S156L and FH Puerto Rico) has been reported in multiple individuals with familial hypercholesterolemia of different origins, some of whom were homozygous for this alteration (Hobbs HH et al. J. Clin. Invest., 1989 Aug;84:656-64; Schuster H et al. Clin Investig, 1993 Feb;71:172-5; Górski B et al. Hum. Genet., 1998 May;102:562-5; Chmara M et al. J. Appl. Genet., 2010;51:95-106; Setia N et al. Atherosclerosis, 2016 Dec;255:31-36; Banerjee P et al. Arterioscler Thromb Vasc Biol, 2019 11;39:2248-2260). In at least two families, this alteration was described to segregate with the disease across multiple generations (Hobbs HH et al. J. Clin. Invest., 1989 Aug;84:656-64; Mohd Nor NS et al. BMC Pediatr, 2019 04;19:106). In addition, functional studies have revealed deficient protein maturation and ligand binding by this alteration (Hobbs HH et al. J. Clin. Invest., 1989 Aug;84:656-64; Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855; Banerjee P et al. Arterioscler Thromb Vasc Biol, 2019 11;39:2248-2260). In addition, this alteration is predicted to be deleterious by in silico analysis. 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	0.78
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.4	D;D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.67
MutPred		0.72		Loss of disorder (P = 0.0252);Loss of disorder (P = 0.0252);.;Loss of disorder (P = 0.0252);
MVP		1.0
MPC		0.76
ClinPred		0.96	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.91
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: rs121908026; hg19: chr19-11216112;