chr2-21006289-G-A

Position:

chr2-21006289-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM5PP5_Very_Strong

The NM_000384.3(APOB):c.10579C>T(p.Arg3527Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000576 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R3527Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

APOB
NM_000384.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:26U:1O:1

Conservation

PhyloP100: 4.09

Variant links:

Genes affected

APOB (HGNC:603): (apolipoprotein B) This gene product is the main apolipoprotein of chylomicrons and low density lipoproteins (LDL), and is the ligand for the LDL receptor. It occurs in plasma as two main isoforms, apoB-48 and apoB-100: the former is synthesized exclusively in the gut and the latter in the liver. The intestinal and the hepatic forms of apoB are encoded by a single gene from a single, very long mRNA. The two isoforms share a common N-terminal sequence. The shorter apoB-48 protein is produced after RNA editing of the apoB-100 transcript at residue 2180 (CAA->UAA), resulting in the creation of a stop codon, and early translation termination. Mutations in this gene or its regulatory region cause hypobetalipoproteinemia, normotriglyceridemic hypobetalipoproteinemia, and hypercholesterolemia due to ligand-defective apoB, diseases affecting plasma cholesterol and apoB levels. [provided by RefSeq, Dec 2019]

APOB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP5

Variant 2-21006289-G-A is Pathogenic according to our data. Variant chr2-21006289-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-21006289-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOB	NM_000384.3 linkuse as main transcript	c.10579C>T	p.Arg3527Trp	missense_variant	26/29	ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5 linkuse as main transcript	c.10579C>T	p.Arg3527Trp	missense_variant	26/29	1	NM_000384.3	ENSP00000233242	P1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000964

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000172

AC:

AN:

250718

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135494

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00131

Gnomad SAS exome

AF:

0.000359

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000707

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000547

AC:

AN:

1461728

Hom.:

Cov.:

AF XY:

0.0000646

AC XY:

AN XY:

727168

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000453

Gnomad4 SAS exome

AF:

0.000383

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000966

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000797

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000165

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:26Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, type B

Pathogenic:7Other:1

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Arg3527Trp variant in APOB has been reported in at least 47 individuals with hypercholesterolemia, segregated with disease in 10 individuals from 2 families (PMID: 27206935, 17087781, 20538126), and has been identified in 0.1253% (25/19946) of East Asian chromosomes, 0.03594% (11/30604) of South Asian chromosomes, and 0.007002% (9/128542) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs144467873). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Animal models in mice have shown that this variant causes hypercholesterolemia (PMID: 9486979). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Two additional pathogenic/likely pathogenic variants, resulting in a different amino acid change at the same position, p.Arg3527Gln and p.Arg3527Leu, have been reported in association with hypercholesterolemia in the literature and ClinVar, supporting that a change at this position may not be tolerated (VariationID: 17890, 440523; PMID: 9486979, 23369702, 28428224). Additionally, the p.Arg3527Trp variant is located in a region of APOB that is essential to protein folding and stability, suggesting that this variant is a functional domain and supports pathogenicity (PMID: 9486979). In summary, this variant meets criteria to be classified as pathogenic for hypercholesterolemia in an autosomal dominant manner based on prevalence of the variant and cosegregation in affected individuals, the location of the variant in a functional domain, and animal models demonstrating a deficient protein. ACMG/AMP Criteria applied: PS4, PP11_strong, PM5, PM1, PS3_moderate, PP3 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 05, 2019	Across a selection of the available literature, the APOB c.10579C>T (p.Arg3527Trp) missense variant, previously reported in the literature as p.Arg3500Trp, has been identified in a heterozygous state in at least 33 individuals with familial hypercholesterolemia, 15 of whom were unrelated (Gaffney et al. 1995; Choong et al. 1997; Tai et al. 1998; Fisher et al. 1999). The p.Arg3527Trp variant was absent from 309 controls and is reported at a frequency of 0.001273 in the East Asian population of the Exome Aggregation Consortium. Arg3527 is located in the LDL receptor-binding domain of the APOB protein. Fisher et al. (1999) demonstrated in human skin fibroblast cells that the p.Arg3527Trp variant protein had lower rates of binding, internalization, and degradation of LDL than wild type levels. Based on the evidence, the p.Arg3527Trp 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. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 29, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Apr 05, 2021	The c.10579C>T variant in APOB is one of the most frequent genetic changes reported in individuals with familial hypercholesterolemia-2 (FCHL2), a condition characterized by very high levels of cholesterol in the blood and an increased risk of developing heart disease, beginning at 40 to 50 years of age. However, reduced penetrance of FCHL2 has been reported in persons with a heterozygous APOB pathogenic variant. This variant (rs144467873) is rare in a large population database (45/282118 total alleles; 0.016%; no homozygotes) and has an entry in ClinVar. Experiments using patient derived skin fibroblast cells that contain the p.Arg3527Trp variant protein had lower rates of binding, internalization, and degradation of LDL than wild type levels. In addition, the proliferation rate of U937 cells containing the p.Arg3527Trp substitution supplied with LDL was fourfold less than wild type controls. We consider this variant to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Jun 27, 2024	ACMG Criteria: PS3, PS4, PM2_P, PM5, PP1, PP3, PP5; Variant was found in heterozygous state -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 22, 2024	This missense variant (also known as p.Arg3500Trp in the mature protein) is located in the beta 2 domain of the APOB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant diminishes binding, uptake and degradation of LDL (PMID: 7627691, 10388479, 11238294). This variant has been reported in numerous individuals affected with familial hypercholesterolemia in multiple populations, the majority being of East Asian ancestry, and has been shown to segregate with the disorder in multiple families (PMID: 7627691, 9191540, 9702952, 10388479, 11238294, 16250003, 21376320, 22294733, 23375686, 23936638, 27206935, 32591292). A different missense variant at the same position, p.Arg3527Gln, is a well established pathogenic variant (Clinvar variation ID 17890). This variant has been identified in 40/276418 chromosomes in the general population by the Genome Aggregation Database (gnomAD). APOB mutations show incomplete penetrance and individuals with APOB mutations may show a less severe phenotype than familial hypercholesterolemia patients with LDLR mutations (PMID: 8141833, 21868016, 21513517). In summary, the mutant APOB protein harboring this variant is functionally defective and has shown significant clinical association with familial hypercholesterolemia. Based on available evidence, this variant is classified as Pathogenic. -

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jan 20, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 27, 2021	This variant has been reported in individuals with familial hypercholesterolemia in the published literature (PMID: 26415676 (2015) and 27765764 (2015)). This variant segregates with disease in multiple families (PMID: 27783906 (2016), 11238294 (2001), and 10388479 (1999)). Assessment of experimental evidence regarding the effect of this variant suggests it is detrimental to normal function (PMID: 11238294 (2001), 10388479 (1999), and 7627691 (1995)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 24, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	APOB: PP1:Strong, PS4, PM5, PS3:Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	May 03, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 16, 2021	Legacy Nomenclature: p.R3500W -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2022	Reported as a common cause of FH among East Asians (Andersen et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate that the variant reduced APOB capacity for binding, uptake, and degradation of LDL (Fisher et al., 1999); Also reported as R3500W due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 9191540, 30217213, 10529757, 31686828, 23375686, 24784157, 7627691, 27919345, 28965616, 30971288, 30592178, 26415676, 24234650, 23936638, 11238294, 11833852, 30420299, 30586733, 30291343, 20538126, 28235710, 29399563, 22294733, 29353225, 31447099, 9702952, 31345425, 10388479, 27765764, 27783906, 16250003, 34037665, 7718024, 34220717, 33418990, 33740630, 32719484, 34426522) -

Hypercholesterolemia, familial, 1

Pathogenic:3Uncertain:1

Uncertain significance, flagged submission	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Aug 22, 2019	- -
Likely pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	Mar 18, 2019	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -

Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 3527 of the APOB protein (p.Arg3527Trp). This variant is present in population databases (rs144467873, gnomAD 0.1%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 7627691, 9191540, 9702952, 11238294, 16250003, 21376320, 22294733, 27206935). It is commonly reported in individuals of East Asian ancestry (PMID: 7627691, 9191540, 9702952, 11238294, 16250003, 21376320, 22294733, 23375686, 23936638, 26415676, 27206935). This variant is also known as R3500W. ClinVar contains an entry for this variant (Variation ID: 40223). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on APOB protein function. This variant disrupts the p.Arg3527 amino acid residue in APOB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2563166, 10388479, 11238294, 24234650). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Sep 19, 2022	The c.10579C>T (p.Arg3527Trp) variant identified in the APOB gene substitutes a well conserved Arginine for Tryptophan at amino acid 3527/4564 (exon 26/29). It is found with low frequency in population databases (gnomADv2.1.1, gnomADv3.1.2, BRAVO-TOPMed, All of Us) with highest allele frequency 8.54e-5 (gnomADv3.1.2, 0 homozygotes), suggesting it is not a common benign variant in the populations represented in those databases. This variant is also referred to as p.Arg3500Trp in literature based off of annotation from mature protein. In silico algorithms predict this variant to be Pathogenic (REVEL;score:0.8539) to the function of the canonical protein. This variant is reported in ClinVar as Pathogenic / Likely Pathogenic (VarID:40223), and has been reported in many affected individuals with familial hypercholesterolemia, and has been shown to segregate with hypercholesterolemia in multiple affected families [PMID:27206935, 21376320, 9702952, 7627691, others]. Functional studies suggest this variant reduces binding, uptake, and degradation of LDL [PMID:7627691,11238294]. Given its presence in many affected individuals in the literature in which it segregates with disease, functional studies showing altered activity, and its low frequency in population databases, the c.10579C>T (p.Arg3527Trp) variant identified in the APOB gene is reported as Pathogenic. -

APOB-related disorder

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 07, 2024	The APOB c.10579C>T variant is predicted to result in the amino acid substitution p.Arg3527Trp. This variant (also known as p.Arg3500Trp) has been reported in many patients with autosomal dominant hypercholesterolemia (see for example Gaffney et al. 1995. PubMed ID: 7627691; Bertolini et al. 2013. PubMed ID: 23375686; Pirillo et al. 2017. PubMed ID: 28965616). Additionally, different substitutions of the same amino acid (p.Arg3527Gln and p.Arg3527Leu) have been reported in many patients with hypercholesterolemia (see for example Soria et al. 1989. PubMed ID: 2563166; Bertolini et al. 2013. PubMed ID: 23375686; Pirillo et al. 2017. PubMed ID: 28965616; Fouchier et al. 2005. PubMed ID: 16250003), suggesting that the amino acid residue p.Arg3527 is important for proper APOB protein function. This variant is reported in 0.13% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Feb 01, 2022	- -

Familial hypercholesterolemia

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 05, 2023	This missense variant (also known as p.Arg3500Trp in the mature protein) is located in the beta 2 domain of the APOB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant diminishes binding, uptake and degradation of LDL (PMID: 7627691, 10388479, 11238294). This variant has been reported in numerous individuals affected with familial hypercholesterolemia in multiple populations, the majority being of East Asian ancestry, and has been shown to segregate with the disorder in multiple families (PMID: 7627691, 9191540, 9702952, 10388479, 11238294, 16250003, 21376320, 22294733, 23375686, 23936638, 27206935, 32591292). A different missense variant at the same position, p.Arg3527Gln, is a well established pathogenic variant (Clinvar variation ID 17890). This variant has been identified in 40/276418 chromosomes in the general population by the Genome Aggregation Database (gnomAD). APOB mutations show incomplete penetrance and individuals with APOB mutations may show a less severe phenotype than familial hypercholesterolemia patients with LDLR mutations (PMID: 8141833, 21868016, 21513517). In summary, the mutant APOB protein harboring this variant is functionally defective and has shown significant clinical association with familial hypercholesterolemia. Based on available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 31, 2018	Variant summary: APOB c.10579C>T (p.Arg3527Trp also known as R3500W) 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 0.00014 in 276418 control chromosomes (gnomAD). c.10579C>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Chiou_2012, Wald_2016). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic" (4x) and once as "uncertain significance." Based on the evidence outlined above, the variant was classified as pathogenic. -

Homozygous familial hypercholesterolemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 02, 2020

The p.Arg3527Trp variant (also referred to in the literature as p.Arg3500Trp) in APOB has been reported in at least 33 individuals with familial hypercholesterolemia, the majority of whom are of East Asian ancestry, and segregated with disease in at least 15 affected relatives from 4 families (Gaffney 1995 PMID: 7627691, Choong 1997 PMID: 9191540, Tai 1998 PMID: 9702952, Fisher 1999 PMID: 10388479, Tai 2001 PMID: 11238294, Yang 2007 PMID: 17964958, Hollandt 2012 PMID: 22294733, Chiou 2010 PMID: 20538126, Chiou 2011 PMID: 21376320, Chiou 2012 PMID: 22353362, Bertolini 2013 PMID: 23375686). This variant has been reported in ClinVar (Variation ID 40223) and has also been identified in 0.12% (25/19946) of East Asian and 0.007% (25/128542) 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. In vitro functional studies provide some evidence that the p.Arg3527Trp variant may impact protein function (Gaffney 1995 PMID: 7627691, Fisher 1999 PMID: 10388479, Tai 2001 PMID: 11238294). Additionally, another variant at this position, p.Arg3527Gln, is a well-established pathogenic variant for FH. In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dominant manner based upon segregation studies, increased prevalence in affected individuals, and pathogenicity of other variants at this position. Please note that pathogenic variants in APOB can have reduced penetrance and a less severe phenotype than disease-causing LDLR or PCSK9 variants (Youngblom and Knowles, GeneReviews, PMID: 24404629). ACMG/AMP Criteria applied: PS4_Strong; PP1_Strong, PS3_Supporting, PM5. -

Familial hypobetalipoproteinemia 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 29, 2022

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2024

The c.10579C>T (p.R3527W) alteration is located in exon 26 (coding exon 26) of the APOB gene. This alteration results from a C to T substitution at nucleotide position 10579, causing the arginine (R) at amino acid position 3527 to be replaced by a tryptophan (W). Based on the available evidence, the APOB c.10579C>T (p.R3527W) alteration is classified as pathogenic for autosomal dominant APOB-related familial hypercholesterolemia; however, its clinical significance for autosomal recessive APOB-related hypobetalipoproteinemia is uncertain. Based on data from the Genome Aggregation Database (gnomAD), the APOB c.10579C>T alteration was observed in 0.02% (45/282,118) of total alleles studied, with a frequency of 0.13% (25/19,946) in the East Asian subpopulation. This alteration, also known as p.R3500W, has been reported in multiple individuals and families with hyperlipidemia from varying ethnic backgrounds (Gaffney, 1995; Choong, 1997; Fisher, 1999; Tai, 1998; Tai, 2001; Chiou, 2011; Bertolini, 2013) and has been reported as a common cause of disease in Asian populations (Chiou, 2011; Chiou, 2016; Chan, 2019). In addition, two alterations at the same codon, p.R3527Q and p.R3527L (reported as p.R3500Q and p.R3500L), have also been associated with familial hypercholesterolemia (Soria, 1989; Fouchier, 2005). This amino acid position is highly conserved in available vertebrate species. In vitro studies have reported this alteration to attenuate protein function (Gaffney, 1995; Tai, 2001). The p.R3527W alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.34

CADD

Uncertain

DANN

Pathogenic

1.0

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.96

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.70

MetaSVM

Uncertain

0.45

MutationTaster

Benign

1.0

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-6.3

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.80

MVP

0.93

MPC

0.28

ClinPred

0.48

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.84

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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