Submissions for variant NM_000527.5(LDLR):c.1003G>A (p.Gly335Ser)

gnomAD frequency: 0.00004  dbSNP: rs544453230

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000238015	SCV004022375	likely pathogenic	Hypercholesterolemia, familial, 1	2023-04-28	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1003G>A (p.Gly335Ser) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PP4, PS3_Supporting and PS4_Supporting 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: PM2 - PopMax MAF = 0.00005431 (0.005431%) in European non-Finnish exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met. PP3 - REVEL = 0.843. It is above 0.75, so PP3 is met. PS4_supporting - variant meets PM2 and was identified in: - 3 unrelated index cases who fulfill Dutch lipid clinic network >=6 from Robarts Research Institute, Canada; - at least 1 index case with Dutch Lipid Clinic Scoring : Definite FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583773.1), France; - 1 index case with DLNC > or = 6 from Bañares et al. 2017 (PMID: 28502510), Argentina; at least 5 unrelated index cases with clinical FH criteria, so PP4 is met. PP4 - variant meets PM2 and was identified in at least 5 unrelated index cases with clinical FH criteria (see PS4_Supporting for details), so PP4 is met. PS3_supporting - Level 3 FS: Hobbs et al. 1992 (PMID: 1301956): Heterozygous patients' fibroblasts, 125I-LDL assays - results: 30-40% LDLR activity. --- activity is below 85% of wild-type, so PS3_Supporting is met.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000215066	SCV000271915	likely pathogenic	Homozygous familial hypercholesterolemia	2021-03-22	criteria provided, single submitter	clinical testing	The p.Gly335Ser variant in LDLR (also described as p.Glu314Ser in the literature) has been reported in at least 14 individuals with hypercholesterolemia: in at least 11 heterozygotes, 1 double heterozygote who also had a pathogenic variant in the PCSK9 gene, and in the compound heterozygous state with another pathogenic LDLR variant in a set of identical twins with homozygous familial hypercholesterolemia (HoFH; Hobbs 1992 PMID: 1301956, Wang 2001 PMID: 11668627, Laurie 2004 PMID: 15556094, Bertolini 2013 PMID: 23375686, Retterer 2015 PMID: 26633542, Abul-Husn 2016 PMID: 28008010, Rabacchi 2016 PMID: 27578127, Wang 2015 PMID: 27765764, Banares 2017 PMID: 28502510, Clinvar Variation ID 183105). It has also been identified in 2 individuals with myocardial infarction (Do 2015 PMID: 25487149, Thomaehlen 2015 PMID: 25647241). In the family with HoFH, this variant segregated with disease (in the compound heterozygous state) in 2 other affected siblings and in the heterozygous state in 2 other affected relatives (Rabacchi 2016 PMID: 27578127). Functional studies provide conflicting evidence on the impact of this variant on the protein (Hobbs 1992 PMID: 1301956, Thormaehlen 2015 PMID: 25647241). Additionally, this variant has been identified in 0.005% (7/128886) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of familial hypercholesterolemia (FH) in the general population. Computational prediction tools and conservation analysis are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PM3, PS4_Moderate, PP1, PP3, PM2_Supporting.
LDLR-LOVD, British Heart Foundation	RCV000238015	SCV000295129	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000238015	SCV000484723	likely pathogenic	Hypercholesterolemia, familial, 1		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	RCV000238015	SCV000503276	likely benign	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1 / Software predictions: Damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000238015	SCV000583773	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000238015	SCV000599356	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	curation
Iberoamerican FH Network	RCV000238015	SCV000748093	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001201392	SCV000819690	pathogenic	Familial hypercholesterolemia	2024-03-16	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 335 of the LDLR protein (p.Gly335Ser). This variant is present in population databases (rs544453230, gnomAD 0.006%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1301956, 11668627, 15556094, 23375686, 27765764, 28502510). This variant is also known as Gly314Ser. ClinVar contains an entry for this variant (Variation ID: 183105). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on LDLR function (PMID: 1301956, 25647241). This variant disrupts the p.Gly335 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 10735632), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001201392	SCV001422749	uncertain significance	Familial hypercholesterolemia	2020-01-22	criteria provided, single submitter	curation	The p.Gly335Ser variant in LDLR has been reported in at least 6 individuals with familial hypercholesterolemia (PMID: 1301956, 11668627, 15556094, 27765764, 27578127, 28008010, 2852510) and has been identified in 0.005431% (7/128886) of European (non-Finnish) chromosomes and 0.005016% (1/19938) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs544453230). This variant has also been reported in ClinVar (PMID: 183105) as likely benign by Centre de Genetique Moleculaire et Chromosomique, as a VUS by the Laboratory for Molecular Medicine, as likely pathogenic by the British Heart Foundation, Roberts Research Institute, Instituto Nacional de Saude Doutor Ricardo Jorge, Iberoamerican FH Network, Invitae, and the Children's Hospital of Philadelphia, and as Pathogenic by U4M - Lille University & CHRU Lille. In vitro functional studies provide some evidence that the p.Gly335Ser variant may not impact protein function (PMID: 25647241). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. 4 affected individuals with this variant have an alternative molecular basis for familial hypercholesterolemia , suggesting that this variant may not be pathogenic (PMID: 27578127). In summary, the clinical significance of the p.Gly335Arg variant is uncertain. ACMG/AMP Criteria applied: PS4_moderate, PP3, BP5, BS3_supporting (Richards 2015).
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001201392	SCV001445927	likely pathogenic	Familial hypercholesterolemia	2019-09-24	criteria provided, single submitter	clinical testing	This variant has been previously reported as a heterozygous change in patients with familial hypercholesterolemia (PMID: 1301956, 23375686). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0028% (8/282,406) and thus is presumed to be rare. The c.1003G>A (p.Gly335Ser) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1003G>A (p.Gly335Ser) variant is classified as Likely Pathogenic.
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000238015	SCV001653615	likely pathogenic	Hypercholesterolemia, familial, 1	2021-05-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001201392	SCV002053218	likely pathogenic	Familial hypercholesterolemia	2024-01-02	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 335 in the EGF precursor homology domain of the LDLR protein. This variant is also known as p.Gly314Ser in the mature protein, and as and as FH Paris-6 in the literature. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Functional studies have shown the mutant protein to exhibits normal LDLR activity in an in vitro high throughput cell-based assay (PMID: 25647241) and mildly reduced activity (30-40% of normal activity) in ex vivo assays using cells from a compound heterozygous carrier individual (PMID: 1301956). This LDLR variant has been reported in over 10 heterozygous individuals affected with familial hypercholesterolemia (PMID: 1301956, 11668627, 15556094, 23375686, 27765764, 28008010, 28502510, 33740630, 34297352). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in two related individuals affected with homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 27578127). This variant has been identified in 8/282406 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	RCV001201392	SCV002522169	likely pathogenic	Familial hypercholesterolemia	2021-08-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399588	SCV002709013	likely pathogenic	Cardiovascular phenotype	2024-11-26	criteria provided, single submitter	clinical testing	The c.1003G>A (p.G335S) alteration is located in exon 7 (coding exon 7) of the LDLR gene. This alteration results from a G to A substitution at nucleotide position 1003, causing the glycine (G) at amino acid position 335 to be replaced by a serine (S). Based on data from gnomAD, the A allele has an overall frequency of 0.003% (8/282406) total alleles studied. The highest observed frequency was 0.005% (7/128886) of European (non-Finnish) alleles. This alteration (legacy nomenclature G314S) has been reported in multiple individuals with concerns for familial hypercholesterolemia (FH) (Hobbs, 1992; Laurie, 2004; Bertolini, 2013; Retterer, 2016; Wang, 2016; Bañares, 2017; Martín-Campos, 2018; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. Internal structural analysis suggests that this variant is anticipated to disrupt a region of known function (Rudenko, 2002; Lo Surdo, 2011). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Revvity Omics, Revvity	RCV000238015	SCV003831276	likely pathogenic	Hypercholesterolemia, familial, 1	2023-02-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000238015	SCV004820248	likely pathogenic	Hypercholesterolemia, familial, 1	2024-03-08	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Gly314Ser in the mature protein and as FH Paris-6) replaces glycine with serine at codon 335 in the EGF precursor homology domain 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 have shown the mutant protein to exhibit normal LDLR activity in an in vitro high throughput cell-based assay (PMID: 25647241) and mildly reduced activity (30-40% of normal activity) in ex vivo assays using cells from a compound heterozygous carrier (PMID: 1301956). This LDLR variant has been reported in over 10 heterozygous individuals affected with familial hypercholesterolemia (PMID: 1301956, 11668627, 15556094, 23375686, 27765764, 28008010, 28502510, 33740630, 34297352). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in two related individuals affected with homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 27578127). This variant has been identified in 8/282406 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000238015	SCV005417593	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing	PM2_Supporting+PS4_Moderate+PP1+PP4+PP3
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000161976	SCV000189551	not provided	not provided		no assertion provided	in vitro
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000238015	SCV000536701	likely pathogenic	Hypercholesterolemia, familial, 1	2014-10-31	no assertion criteria provided	research