19-11120143-C-T

Variant names:

• chr19-11120143-C-T
• rs746118995
• NM_000527.5:c.1897C>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000527.5(LDLR):​c.1897C>T​(p.Arg633Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,613,870 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. R633H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:27
• Conservation: PhyloP100: 1.45
• Publications: 16 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 17 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 20 uncertain in NM_000527.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-11120144-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 226380.
• 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, 0.989
• PP5: Variant 19-11120143-C-T is Pathogenic according to our data. Variant chr19-11120143-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 226379.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.1897C>T	p.Arg633Cys	missense_variant	Exon 13 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1897C>T	p.Arg633Cys	missense_variant	Exon 13 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251490 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000328 AC: 48 AN: 1461708 Hom.: 0 Cov.: 33 AF XY: 0.0000234 AC XY: 17 AN XY: 727170

African (AFR) AF: 0.0000299 AC: 1 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000351 AC: 39 AN: 1111844

Other (OTH) AF: 0.0000331 AC: 2 AN: 60394

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152162 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74326

African (AFR) AF: 0.0000241 AC: 1 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:27

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:17

Mar 30, 2017

U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Jan 09, 2015

Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Nov 05, 2016

Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 23, 2021

Clinical Genomics Laboratory, Stanford Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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] -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NA -

-

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 14, 2018

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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 -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS3_Moderate+PS4+PP4+PM3 -

Oct 11, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM1, PM2, PM5, PP1 -

-

Robarts Research Institute, Western University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Aug 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Aug 02, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2013

Arcensus

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial hypercholesterolemia Pathogenic:5

-

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Nov 08, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Aug 01, 2023

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Feb 18, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with cysteine at codon 633 of the LDLR protein. This variant is also known as p.Arg612Cys in the mature protein. This variant alters a conserved arginine residue in the LDLR type B repeat 6 of the LDLR protein (a.a. 616-658), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function. 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 more than 20 individuals affected with familial hypercholesterolemia (PMID: 9259195, 15241806, 16159606, 17094996, 17539906, 19446849, 19843101, 20538126, 22698793, 23375686, 27765764, 28028493, 28235710, 31491741, 34037665, 37967952). 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. -

not provided Pathogenic:2

Feb 21, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 26, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Homozygous familial hypercholesterolemia Pathogenic:1

Mar 04, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

LDLR-related disorder Pathogenic:1

Jul 22, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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. -

Cardiovascular phenotype Pathogenic:1

Apr 03, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;.;.;.;.;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;.;.;.;.;M
PhyloP100		1.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-7.0	D;D;D;D;D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.99	D;.;.;.;.;.
Vest4		0.67
MutPred		0.96		Gain of catalytic residue at L634 (P = 0.0077);Gain of catalytic residue at L634 (P = 0.0077);.;.;.;Gain of catalytic residue at L634 (P = 0.0077);
MVP		1.0
MPC		0.95
ClinPred		0.95	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: 10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs746118995; hg19: chr19-11230819;