19-11116936-C-T
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS4PP1_StrongPM2PP3PP4
This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.1783C>T (p.Arg595Trp) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS4, PP1_Strong, PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PS4 - Variant meets PM2. Variant identified in 12 index cases.PP1_strong - 10 informative meioses identified by Laboratory of Genetics and Molecular Cardiology.PM2 - PopMax MAF = 0.00001548 (0.0015%) in European non-Finnish (gnomAD v2.1.1). PP3 - REVEL: 0,89. PP4 - Variant meets PM2. Variant identified in 12 index cases fulfilling validated clinical criteria for FH (6 cases with Simon-Broome or DLCN criteria from Ambry Genetics; 2 cases with Simon-Broome from Color laboratory; 3 cases with Simon-Broome criteria from Laboratory of Genetics and Molecular Cardiology; 1 case with Simon-Broome criteria from GeneDx). LINK:https://erepo.genome.network/evrepo/ui/classification/CA023581/MONDO:0007750/013
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
Publications
- hypercholesterolemia, familial, 1Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
- homozygous familial hypercholesterolemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 12 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LDLR | NM_000527.5 | c.1783C>T | p.Arg595Trp | missense_variant | Exon 12 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LDLR | ENST00000558518.6 | c.1783C>T | p.Arg595Trp | missense_variant | Exon 12 of 18 | 1 | NM_000527.5 | ENSP00000454071.1 |
Frequencies
GnomAD3 genomes 0.0000263 AC: 4AN: 152058Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00000398 AC: 1AN: 251488 AF XY: 0.00000736 show subpopulations
GnomAD4 exome AF: 0.0000150 AC: 22AN: 1461856Hom.: 0 Cov.: 34 AF XY: 0.0000151 AC XY: 11AN XY: 727230 show subpopulations
Age Distribution
GnomAD4 genome 0.0000263 AC: 4AN: 152058Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74270 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:13Uncertain:4
Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc).;Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
NM_000527.5(LDLR):c.1783C>T (p.Arg595Trp) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS4, PP1_Strong, PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PS4 - Variant meets PM2. Variant identified in 12 index cases. PP1_strong - 10 informative meioses identified by Laboratory of Genetics and Molecular Cardiology. PM2 - PopMax MAF = 0.00001548 (0.0015%) in European non-Finnish (gnomAD v2.1.1). PP3 - REVEL: 0,89. PP4 - Variant meets PM2. Variant identified in 12 index cases fulfilling validated clinical criteria for FH (6 cases with Simon-Broome or DLCN criteria from Ambry Genetics; 2 cases with Simon-Broome from Color laboratory; 3 cases with Simon-Broome criteria from Laboratory of Genetics and Molecular Cardiology; 1 case with Simon-Broome criteria from GeneDx).
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial hypercholesterolaemia 1 (FH; MIM#143890). (I) 0108 - This gene is associated with both recessive and dominant disease. Variants have been reported in heterozygous, compound heterozygous and homozygous states with the recessive disease being more severe (OMIM, PMID: 10978268). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 24404629). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2 & v3) <0.01 (5 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (11 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated low density lipoprotein receptor class B domain (DECIPHER). (I) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Two alternative missense variants at the same position have been classified as pathogenic or likely pathogenic by an expert panel in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogneic by an expert panel in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
This missense variant (also known as p.Arg574Trp in the mature protein) replaces arginine with tryptophan at codon 595 in the fifth LDLR type B repeat of 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 20 individuals affected with familial hypercholesterolemia (PMID: 11737238, 16250003, 20538126, 25461735, 28502510, 32044282, 32331935, 34037665, 34176852; Color internal data), including three homozygous individuals with severe phenotype (PMID: 27784735). This variant has been identified in 2/282862 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same codon (p.Arg595Leu and Arg595Gln) have been reported in individuals affected with familial hypercholesterolemia (ClinVar variation ID: 252029, 183126), suggesting that arginine at this position is a functionally and clinically important residue. Based on the available evidence, this variant is classified as Pathogenic.
Familial hypercholesterolemia Pathogenic:6
The c.1783C>T (p.Arg595Trp) variant, also known as p.Arg574Trp in LDLR gene that encodes for low density lipoprotein receptor, has been identified in several unrelated individuals (>10) who fulfill the clinical criteria of familial hypercholesterolemia and segregated with disease in ten informative meioses (PMID:11737238, 16250003, 20538126, 25461735, 28502510). In-silico computational prediction tools suggest that the p.Arg595Trp variant may have deleterious effect on the protein function (REVEL score: 0.89). This variant is found to be rare (2/282862 chromosomes) in the general population database, gnomAD. This variant is interpreted as pathogenic by multiple submitters in the ClinVar database including the ClinGen expert panel (ClinVar ID: 161290). Another amino acid substitution at same position (p.Arg595Gln) has been classified as pathogenic by the ClinGen expert panel (ClinVar ID:183126). Therefore, the c.1783C>T (p.Arg595Trp) variant in LDLR gene is classified as pathogenic.
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 595 of the LDLR protein (p.Arg595Trp). This variant is present in population databases (rs373371572, gnomAD 0.002%). This missense change has been observed in individuals with familial hypercholesterolaemia (PMID: 11737238, 16250003, 20538126, 25461735, 27784735). ClinVar contains an entry for this variant (Variation ID: 161290). 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%. This variant disrupts the p.Arg595 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15256764, 15359125, 16250003, 18718593, 25437892, 25487149, 27497240, 28502510). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Variant summary: LDLR c.1783C>T (p.Arg595Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251488 control chromosomes. c.1783C>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia in the homozygous and compound heterozygous state (Mozas_2004, Junyent_2010, Damgaard_2005, Chiou_2012, Pek_2018, Pirillo_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments, three as VUS, six as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
This missense variant replaces arginine with tryptophan at codon 595 of the LDLR protein. This variant is also known as p.Arg574Trp in the mature protein. This variant alters a conserved arginine residue in the LDLR type B repeat 5 of the LDLR protein (a.a. 572-615), 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 20 individuals affected with familial hypercholesterolemia (PMID: 11737238, 16250003, 20538126, 25461735, 28502510, 32044282, 32331935, 34037665, 34176852, 37967952; Color internal data), including three homozygous individuals with severe phenotype (PMID: 27784735). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (ClinVar SCV001960931.1). This variant has been identified in 2/282862 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same codon (p.Arg595Leu and Arg595Gln) have been reported in individuals affected with familial hypercholesterolemia (ClinVar variation ID: 252029, 183126), suggesting that arginine at this position is a functionally and clinically important residue. Based on the available evidence, this variant is classified as Pathogenic.
The c.1783C>T;p.(Arg595Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar: 161290; PMID: 11737238; 25461735; 27784735; 16250003; 20538126) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Ldl_recept_b) - PM1. The variant is present at low allele frequencies population databases (rs373371572 - gnomAD 0.0002631%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. Pathogenic missense variant in this residue have been reported (ClinVar ID: 252029 - c.1784G>T;p.(Arg595Leu)) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 11737238; 16250003; 20538126) - PP1_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
The LDLR c.1783C>T p.(Arg595Trp) variant has been reported in >=10 FH patients meeting clinical criteria, including patients where secondary causes of high cholesterol were excluded (PS4_STRONG, PP4_SUPPORTING; PMIDs 11737238, 15241806, 16250003, 20538126, 28965616, 29353225, 34176852, 36226792, 37967952, ClinGen FH VCEP data, internal data). This variant was found to segregate with FH in >=6 informative meioses (PP1_STRONG; ClinGen FH VCEP data). Level 1 functional study in HEK293 cells demonstrated reduced binding (<70% of wild-type) and defective receptor recycling (PS3_STRONG; PMID 30583242). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001548 in the European (non-Finnish) population, which is lower than the ClinGen FH VCEP threshold (=<0.0002) for PM2_MODERATE. The REVEL score is 0.890 (PP3_SUPPORTING). Based on the evidence listed above, we have classified this variant as Pathogenic.
not provided Pathogenic:3
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported as a pathogenic variant by ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel (ClinVar Variant ID#171218; SCV001960931.1); Also known as p.(R574W); This variant is associated with the following publications: (PMID: 25637381, 28502510, 29172679, 28965616, 15823288, 16250003, 28502495, 30586733, 31491741, 31447099, 33740630, 34037665, 29353225, 32331935, 11737238, 15241806, 27578128, 30583242, 34906454, 34526433, 33994402, 34176852, 20538126, 25461735, 27784735)
Cardiovascular phenotype Pathogenic:1
The c.1783C>T (p.R595W) alteration is located in coding exon 12 of the LDLR gene. This alteration results from a C to T substitution at nucleotide position 1783, causing the arginine (R) at amino acid position 595 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (2/282862) total alleles studied. The highest observed frequency was 0.002% (2/129168) of European (non-Finnish) alleles. This variant has been reported in several individuals with familial hypercholesterolemia (FH) from varying ethnic backgrounds (Descamps, 2001; Damgaard, 2005; Tejedor, 2005; Fouchier, 2005; Chiou, 2010; Jannes, 2015; Bañares, 2017; Pirillo, 2017; Pek, 2018). Another alteration at the same codon, p.R595Q (c.1784G>A), has also been detected in individuals with FH (Fouchier, 2005). This amino acid position is highly conserved in available vertebrate species. Functional studies of this variant demonstrated reduced binding capacity and receptor recycling (Guo, 2019). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Hypercholesterolemia Uncertain:1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at