Submissions for variant NM_000527.5(LDLR):c.1897C>T (p.Arg633Cys)

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211568	SCV000295745	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000211568	SCV000484757	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000211568	SCV000540848	likely pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000590441	SCV000544682	pathogenic	Familial hypercholesterolemia	2025-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 633 of the LDLR protein (p.Arg633Cys). This variant is present in population databases (rs746118995, gnomAD 0.003%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 9259195, 15241806, 19446849, 19538517, 19843101, 21376320, 22698793, 23375686). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. This variant is also known as p.Arg612Cys. ClinVar contains an entry for this variant (Variation ID: 226379). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
GeneDx	RCV000486101	SCV000567421	pathogenic	not provided	2022-01-26	criteria provided, single submitter	clinical testing	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 suggest a damaging effect as Western blotting showed decreased expression and reduced LDL uptake suggesting a negative effect on LDLR receptor recycling (Galicia-Garcia et al., 2020); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#226379; ClinVar); Also reported as R612C due to alternate nomenclature; This variant is associated with the following publications: (PMID: 28349888, 27680772, 9259195, 15241806, 27578128, 28235710, 19843101, 16159606, 20538126, 23375686, 19446849, 18700895, 17539906, 22698793, 21376320, 19538517, 17094996, 32015373, 31447099, 31491741, 30586733, 31589614, 34037665, 33087929, 32041611, 32719484)
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000211568	SCV000583906	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000211568	SCV000588622	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000211568	SCV000607653	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590441	SCV000697214	pathogenic	Familial hypercholesterolemia	2016-11-08	criteria provided, single submitter	clinical testing	Variant summary: The LDLR c.1897C>T (p.Arg633Cys) variant, alternatively also known as R612C, is located in EGF precursor homology domain of the LDLR protein (Mozas_2004, Bertolini_2013) and 4/4 in silico tools predict a damaging outcome for this substitution. This variant is absent in 121614 control chromosomes including broad and large populations from ExAC. In literature, this variant is widely reported as a pathogenic variant and is found in several FH patients. Other missense variants in this codon, p.Arg633Leu and p.Arg633His, have been reported as FH patients and are classified as pathogenic/likely pathogenic in ClinVar, suggesting that the codon p.Arg633 is mutational hot-spot. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000211568	SCV000839998	likely pathogenic	Hypercholesterolemia, familial, 1	2018-01-14	criteria provided, single submitter	clinical testing	The c.1897C>T (p.Arg633Cys) variant in the LDLR gene has been reported in several unrelated individuals with familial hypercholesterolemia (PMID: 9259195, 15241806, 19446849, 19843101, 21376320, 22698793, 23375686). Moreover, two other variants at the same residue (p.Arg633His, and p.Arg633Leu) have also been described in multiple individuals with familial hypercholesterolemia (PMID: 16250003, 22390909) suggesting that the Arg633 residue is critical for normal functioning of the LDLR protein. In light of the currently available data this variant in the LDLR gene is classified likely pathogenic
Color Diagnostics, LLC DBA Color Health	RCV000590441	SCV000909183	pathogenic	Familial hypercholesterolemia	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Arg612Cys in the mature protein) replaces arginine with cysteine at codon 633 in the LDLR type B repeat 6 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). A functional study using transfected LDLR-deficient CHO-ldlA7 cells has shown that this variant causes a significant reduction in LDLR expression and activity (PMID: 32015373). This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 9259195, 15241806, 16159606, 17094996, 17539906, 19446849, 19843101, 20538126, 22698793, 23375686, 27765764, 28028493, 28235710, 31491741). This variant has also been observed in compound heterozygous and homozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 17094996, 19538517, 27784735), indicating that this variant contributes to disease. This variant has been identified in 3/251490 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg633His, is considered to be disease-causing (ClinVar variation ID: 226380), suggesting that arginine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000211568	SCV000914827	pathogenic	Hypercholesterolemia, familial, 1	2017-04-28	criteria provided, single submitter	clinical testing	The LDLR c.1897C>T (p.Arg633Cys) variant has been reported in at least eight studies and is found in a total of at least 11 individuals with familial hypercholesterolemia, including one who carried the variant in a compound heterozygous state along with a deletion and in a heterozygous state in ten individuals (Day et al. 1997; Mozas et al. 2004; Taylor et al. 2007; Guardamagna et al. 2009; Taylor et al. 2009; Chiou et al. 2010; Tichý et al. 2012; Bertolini et al. 2013). The p.Arg633Cys variant was absent from 100 controls, and is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium, in a region of good sequence coverage, and hence is presumed to be rare. Based on the evidence, the p.Arg633Cys variant is classified as pathogenic for familial hypercholesterolemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000826210	SCV000967775	likely pathogenic	Homozygous familial hypercholesterolemia	2019-03-04	criteria provided, single submitter	clinical testing	The p.Arg633Cys variant in LDLR has been reported in at least 11 individuals with familial hypercholesterolemia (FH), including one homozygote (Day 1997, Mozas 2004, Guardamagna 2009, Taylor 2009, Chiou 2011, Tichy 2012, Bertolini 2013, Xiang 2017, Medieros 2017). This variant has been reported in ClinVar (Variation ID: 226379) and has also been identified in 1/30782 South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Arg833Cys variant may impact the protein. Two other variants at this amino acid position have been reported in at least 4 individuals with FH (p.Arg633Leu and p.Arg633His). In summary, although additional studies are required to fully establish its clinical significance, the p.Arg633Cys variant is likely pathogenic. ACMG/AMP Criteria applied: PS4_Moderate, PM2, PM5_Supporting, PP3.
Revvity Omics, Revvity	RCV000211568	SCV002017133	pathogenic	Hypercholesterolemia, familial, 1	2022-08-02	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000486101	SCV002502727	pathogenic	not provided	2022-02-21	criteria provided, single submitter	clinical testing
Arcensus	RCV000211568	SCV002564559	pathogenic	Hypercholesterolemia, familial, 1	2013-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408918	SCV002722562	pathogenic	Cardiovascular phenotype	2024-04-03	criteria provided, single submitter	clinical testing	The c.1897C>T (p.R633C) alteration is located in exon 13 (coding exon 13) of the LDLR gene. This alteration results from a C to T substitution at nucleotide position 1897, causing the arginine (R) at amino acid position 633 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (3/251490) total alleles studied. The highest observed frequency was 0.003% (1/30616) of South Asian alleles. This variant (also known as p.R612C) has been reported in numerous individuals and cohorts with familial hypercholesterolemia (FH) (Day, 1997; Sánchez-Hernández, 2016; Wang, 2016). Alternate amino acid substitutions at this codon, p.R633L and p.R633H, have also been reported in individuals with FH (Fouchier, 2005). Based on the available evidence, this alteration is classified as pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000211568	SCV003799113	pathogenic	Hypercholesterolemia, familial, 1	2022-10-11	criteria provided, single submitter	clinical testing	PS3, PM1, PM2, PM5, PP1
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000590441	SCV004046251	pathogenic	Familial hypercholesterolemia		criteria provided, single submitter	clinical testing	This variant is also referred to as p.Arg612Cys in the literature. This variant has been reported as a heterozygous change in individuals with features of familial hypercholesterolemia (PMID: 28349888, 27680772, 9259195, 15241806, 27578128, 21376320, 28235710). Functional studies have shown that the c.1897C>T (p.Arg633Cys) variant results in abnormal function of the LDLR protein (PMID: 32015373). The c.1897C>T (p.Arg633Cys) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (3/251490). It affects a moderately conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Different missense variants involving the same residue (p.Arg633His and p.Arg633Leu) have been previously reported in individuals with familial hypercholesterolemia (ClinVar Variation ID: 226380, 252107). Based on the available evidence, the c.1897C>T (p.Arg633Cys) variant is classified as Pathogenic.
All of Us Research Program, National Institutes of Health	RCV000211568	SCV004818464	pathogenic	Hypercholesterolemia, familial, 1	2024-08-05	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Arg612Cys in the mature protein) replaces arginine with cysteine at codon 633 in the LDLR type B repeat 6 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). A functional study using transfected LDLR-deficient CHO-ldlA7 cells has shown that this variant causes a significant reduction in LDLR expression and activity (PMID: 32015373). This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 9259195, 15241806, 16159606, 17094996, 17539906, 19446849, 19843101, 20538126, 22698793, 23375686, 27765764, 28028493, 28235710, 31491741). This variant has also been observed in compound heterozygous and homozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 17094996, 19538517, 27784735), indicating that this variant contributes to disease. This variant has been identified in 3/251490 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg633His, is considered to be disease-causing (ClinVar variation ID: 226380), suggesting that arginine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000590441	SCV005045753	pathogenic	Familial hypercholesterolemia	2023-08-01	criteria provided, single submitter	clinical testing	The c.1897C>T (p.Arg633Cys) variant in the LDLR gene is located on the exon 13 and is predicted to replace arginine with cysteine at codon 633 (p.Arg633Cys). The variant has been identified in more than 10 unrelated individuals with familial hypercholesterolemia (FH) (PMID: 27680772, 28235710, 28349888, 31893465, 21376320, 22698793, 15241806, 17094996). Other variants disrupting the same amino acid (p.Arg633Leu, p.Arg633His) have been interpreted as likely pathogenic (ClinVar ID: 252107, 226380). The variant is rare in the general population according to gnomAD (3/251490). Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.845). Therefore, the c.1897C>T (p.Arg633Cys) variant of LDLR has been classified as pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000211568	SCV005061045	pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing	NA
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000211568	SCV005417048	pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing	PM2_Supporting+PS3_Moderate+PS4+PP4+PM3
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211568	SCV000268648	pathogenic	Hypercholesterolemia, familial, 1	2015-01-09	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211568	SCV000606552	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV003407739	SCV004113889	pathogenic	LDLR-related disorder	2024-07-22	no assertion criteria provided	clinical testing	The LDLR c.1897C>T variant is predicted to result in the amino acid substitution p.Arg633Cys. This variant (also reported as c.Arg612Cys in the literature) has been reported in many unrelated individuals with familial hypercholesterolemia (Mozas et al. 2004. PubMed ID: 15241806; Chiou et al. 2011. PubMed ID: 21376320; Tichý et al. 2012. PubMed ID: 22698793; Day et al. 1997. PubMed ID: 9259195, referred to as R612C; Bertolini et al. 2013. PubMed ID: 23375686, supplementary data; Di Taranto et al. 2019. PubMed ID: 30710474, supplementary data; Dron et al. 2020. PubMed ID: 32041611; Sturm et al. 2021. PubMed ID: 34037665, supplementary data; Futema et al. 2017. PubMed ID: 28349888). In vitro analysis of this variant indicated that this variant results in diminished LDLR expression and activity (Galicia-Garcia et al. 2020. PubMed ID: 32015373). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. This variant has been reported in ClinVar by many outside laboratories as likely pathogenic or pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/226379/). Two other amino acid substitutions at this position (p.Arg633His and p.Arg633Leu) have also been reported in individuals with hypercholesterolemia (Fouchier et al. 2005. PubMed ID: 16250003; Di Taranto et al. 2021. PubMed ID: 34297352). In summary, we categorize c.1897C>T (p.Arg633Cys) as pathogenic.
Clinical Genomics Laboratory, Stanford Medicine	RCV000211568	SCV004231906	pathogenic	Hypercholesterolemia, familial, 1	2021-09-23	no assertion criteria provided	clinical testing	The p.Arg633Cys variant in the LDLR gene has been reported in at least 10 unrelated individuals with familial hypercholesterolemia (Day et al., 1997; Mozas et al., 2004; Graham et al., 2005; Tosi et al., 2007; Guardamagna et al., 2009; Tichý et al., 2012; Hori et al., 2019; Xiang et al., 2019). Additionally, this variant was found in the compound heterozygous state with a multi-exon deletion in an individual with suspected homozygous familial hypercholesterolemia (Taylor et al., 2009). This variant is also referred to as R612C in the literature. Notably, two different amino acid changes (p.Arg633Leu, p.Arg633His) at this residue have been previously reported in multiple unrelated individuals. This variant has been identified in 3/251,490 chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with the prevalence of familial hypercholesterolemia. A functional study of p.Arg633Cys showed reduced LDLR expression and reduced LDL binding activity, supporting a deleterious effect to the protein (Galicia-Garcia et al., 2020). Computational tools predict that this variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Arg633Cys variant as pathogenic for autosomal dominant familial hypercholesterolemia based on the information above. [ACMG evidence codes used: PS4; PM2; PM3; PS3_Supporting; PP3]