19-11113608-G-A

Position:

• chr19-11113608-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3 PP4 PS4 PP1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1432G>A (p.Gly478Arg) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_strong, PS4, PM2, PP3 and PP4) 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: PP1_strong - variant segregates with FH phenotype in 10 informative meiosis from 4 families from 2 labs:- Laboratory of Genetics and Molecular Cardiology - Data from 1 family: 2 relatives positive for variant with LDL-C >75th percentile, 1 relative negative for variant with LDL-C <50th percentile;- Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge - Data from 3 families. F1: 3 relatives with the phenotype are positive for the variant plus 1 relative without the phenotype is negative for the variant. F2: 1 relative with the phenotype and positive for the variant plus 1 relative without the phenotype is negative for the variant. F3: 1 relative with the phenotype is positive for the variant.so PP1_Strong is metPS4 - variant meets PM2 and was identified in at least 11 unrelated index cases who fulfill clinical FH criteria from different labs:- 1 case with Simon-Broome criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); - 1 case with DLCN score >= 6 from Color Health, Inc; - 4 unrelated cases with DLCN score >= 6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); - 4 unrelated cases with Simon-Broome criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge; - 1 case with DLCN score >= 6 from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory),so PS4 is metPM2 - PopMax MAF = 0.0001234 (0.01234%) in African/African-American exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met.PP3 - REVEL = 0.985. It is above 0.75, so PP3 is met.PP4 - variant meets PM2 and was identified in at least 11 unrelated index cases who fulfill clinical FH criteria from different labs (see details in PS4), so PP4 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023495/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:21 U:5
• Conservation: PhyloP100: 8.03

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1432G>A	p.Gly478Arg	missense_variant	10/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1432G>A	p.Gly478Arg	missense_variant	10/18	1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000279 AC: 7 AN: 251112 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135808

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461736 Hom.: 0 Cov.: 35 AF XY: 0.00000688 AC XY: 5 AN XY: 727182

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74292

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000567

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21 Uncertain:5

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:11 Uncertain:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Sep 19, 2017	This c.1432G>A (p.Gly478Arg) variant in the LDLR gene has been reported in multiple patients with familial hypercholesterolemia (PMID: 1301956, 7573037, 9763532, 11810272). Functional studies have indicated that the p.Gly478Arg variant LDLR protein has 2-5% receptor activity compared to wild-type LDLR protein (PMID: 1301956). The c.1432G>A variant is extremely rare in the general population and glycine at position 478 of the LDLR protein is highly evolutionarily conserved. The c.1432G>A (p.Gly478Arg) variant in the LDLR gene is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	research	Cardiovascular Biomarker Research Laboratory, Mayo Clinic	Aug 31, 2015	MAF =<0.3%, likely pathogenic based on the integrative in-silico score, DLCN criteria >=3; LDL-C >=160 mg/dL, previously reported as P/LP in the literature -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 20, 2023	This missense variant replaces glycine with arginine at codon 478 and alters a conserved glycine residue in the second LDLR type B repeat of the EGF precursor homology domain of the LDLR protein (a.a. 439-485) where pathogenic missense variants are found enriched (ClinVar-LDLR). This variant is also known as p.Gly457Arg in the mature protein sequence and as FH New York-2 and FH Fin-9 in the literature. 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 that this variant causes a defect in protein transport and recycling, and a decreased LDLR activity (PMID: 1301956, 32695144). This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 1301956, 7573037, 9763532, 11810272, 22883975, 25618577, 32143996, 32220565, 32331935; Color internal data). In addition, this variant has been shown to segregate with disease in six affected individuals from two families and was absent in four unaffected family members (PMID: 24627126), as well as in 10 informative meiosis from 4 unpublished families (ClinVar variation ID: 161277; accession ID: SCV002506334.1). This variant has been identified in 7/251112 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 26, 2022	- -
Uncertain significance, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/208 non-FH alleles; 0/50 normolipidemic individuals; 0/100 healthy control individuals -
Uncertain significance, 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	Dec 16, 2016	subjects mutated among 2600 FH index cases screened = 2 / FH-New-York-2, 5 to 15% LDLR activity/Software predictions: Conflicting -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Uncertain significance, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Uncertain significance, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Jun 27, 2008	- -
Pathogenic, no assertion criteria provided	research	Medical Laboratory Center, Huzhou Maternal and Child Health Hospital	-	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Dec 14, 2021	The NM_000527.5(LDLR):c.1432G>A (p.Gly478Arg) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_strong, PS4, PM2, PP3 and PP4) 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: PP1_strong - variant segregates with FH phenotype in 10 informative meiosis from 4 families from 2 labs: - Laboratory of Genetics and Molecular Cardiology - Data from 1 family: 2 relatives positive for variant with LDL-C >75th percentile, 1 relative negative for variant with LDL-C <50th percentile; - Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge - Data from 3 families. F1: 3 relatives with the phenotype are positive for the variant plus 1 relative without the phenotype is negative for the variant. F2: 1 relative with the phenotype and positive for the variant plus 1 relative without the phenotype is negative for the variant. F3: 1 relative with the phenotype is positive for the variant. so PP1_Strong is met PS4 - variant meets PM2 and was identified in at least 11 unrelated index cases who fulfill clinical FH criteria from different labs: - 1 case with Simon-Broome criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); - 1 case with DLCN score >= 6 from Color Health, Inc; - 4 unrelated cases with DLCN score >= 6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); - 4 unrelated cases with Simon-Broome criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge; - 1 case with DLCN score >= 6 from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory), so PS4 is met PM2 - PopMax MAF = 0.0001234 (0.01234%) in African/African-American exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met. PP3 - REVEL = 0.985. It is above 0.75, so PP3 is met. PP4 - variant meets PM2 and was identified in at least 11 unrelated index cases who fulfill clinical FH criteria from different labs (see details in PS4), so PP4 is met. -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

Familial hypercholesterolemia Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 19, 2023	Variant summary: LDLR c.1432G>A (p.Gly478Arg) 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 2.8e-05 in 251112 control chromosomes (gnomAD). c.1432G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Koivisto_1995, Chiou_2010, Chiou_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. The following publications have been ascertained in the context of this evaluation (PMID: 20538126, 28502495, 7573037). 19 ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance (n=4), likely pathogenic (n=10) and pathogenic (n=5, including one expert panel, ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jan 26, 2023	The c.1432G>A (p.Gly478Arg) variant in the LDLR gene is located on the exon 10 and is predicted to replace the glycine with arginine at codon 478 (p.Gly478Arg). The variant has been reported in more than 10 unrelated individuals affected with familial hypercholesterolemia (PMIDs: 27206935, 27680772, 32331935). Another variant disrupting the same amino acid (p.Gly478Glu) has been interpreted as likely pathogenic (ClinVar ID: 440642). The p.Gly478Arg variant has been reported in ClinVar (ID: 161277) and reviewed as a pathogenic variant by the ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel. This variant has been observed by different laboratories to segregate with disease in over 10 meioses of 4 families according to the ClinGen Expert Panel. This variant is rare in the general population according to gnomAD (7/251112). Computational prediction algorithms suggest a deleterious impact (REVEL score 0.985). Therefore, the c.1432G>A (p.Gly478Arg) variant of LDLR has been classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 478 of the LDLR protein (p.Gly478Arg). This variant is present in population databases (rs144614838, gnomAD 0.01%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 17087781, 17765246, 21376320, 22353362, 23064986, 27206935, 30592178; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Gly457Arg. ClinVar contains an entry for this variant (Variation ID: 161277). 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%. This variant disrupts the p.Gly478 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 27824480), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 13, 2023	This missense variant replaces glycine with arginine at codon 478 and alters a conserved glycine residue in the second LDLR type B repeat of the EGF precursor homology domain of the LDLR protein (a.a. 439-485) where pathogenic missense variants are found enriched (ClinVar-LDLR). This variant is also known as p.Gly457Arg in the mature protein sequence and as FH New York-2 and FH Fin-9 in the literature. 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 that this variant causes a defect in protein transport and recycling, and a decreased LDLR activity (PMID: 1301956, 32695144). This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 1301956, 7573037, 9763532, 11810272, 22883975, 25618577, 32143996, 32220565, 32331935; Color internal data). In addition, this variant has been shown to segregate with disease in six affected individuals from two families and was absent in four unaffected family members (PMID: 24627126), as well as in 10 informative meiosis from 4 unpublished families (ClinVar variation ID: 161277; accession ID: SCV002506334.1). This variant has been identified in 7/251112 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 12, 2020	- -

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Nov 20, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2024	Published functional studies suggest impaired LDLR localization and LDL uptake (PMID: 32695144); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as FH New York-2, FH Finn-9, and G457R; This variant is associated with the following publications: (PMID: 23064986, 24055113, 25637381, 30592178, 15199436, 11810272, 18325082, 27680772, 17765246, 15556092, 28145427, 19118540, 9763532, 20538126, 29245966, 22883975, 29261184, 29874871, 1301956, 24507775, 27206935, 21376320, 19318025, 30526649, 17087781, 7573037, 37409534, 36226792, 35130036, 35913489, 35480308, 33955087, 32220565, 8535447, 29292049, 31447099, 32331935, 33994402, 32143996, LinJL2022, 33740630, 34037665, 28126585, 32695144) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Sep 24, 2019	- -

Homozygous familial hypercholesterolemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 26, 2019

The p.Gly478Arg (also called p.Gly457Arg) variant in LDLR has been reported in the heterozygous state in >15 individuals with hypercholesterolemia, and segregated with disease in at least 4 relatives from these families (Hobbs 1992, Koivisto 1995, Bourbon 2008, Alonso 2009, Ahmad 2012, Hooper 2012, Lange 2014, Safaro 2017, ClinVar: Variation ID 161277). The variant has also been reported in two individuals who were compound heterozygous for this variant and a second variant in LDLR (Mak 1998, Chiou 2010). Additionally, another nucleotide change (c.1432G>C) leading to the same amino acid change has been reported in 2 individuals with FH, one of whom was homozygous for the variant (Fouchier 2005, Widhalm 2017). In vitro functional studies provide some evidence that the p.Gly478Arg variant may impact protein function (Hobbs 1992). This variant has been also been identified in 2/17246 East Asian chromosomes and 2/16208 African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Gly478Arg variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Gly478Arg variant is likely pathogenic. The ACMG/AMP criteria applied: PS4, PP1, PP3, PS3_Supporting. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2024

The p.G478R pathogenic mutation (also known as c.1432G>A), located in coding exon 10 of the LDLR gene, results from a G to A substitution at nucleotide position 1432. The glycine at codon 478 is replaced by arginine, an amino acid with dissimilar properties. This variant (also described as legacy p.G457R) has been described in several patients with familial hypercholesterolemia (FH) (Koivisto UM et al. Am J Hum Genet. 1995;57:789-97; Mak YT et al. Arterioscler Thromb Vasc Biol. 1998;18:1600-5; Bourbon M et al. Atherosclerosis. 2008;196:633-42; Chiou KR et al. J Clin Lipidol. 2016;10(3):490-6; Tada H et al. J Clin Lipidol Dec;12:397-402.e2; Hartgers ML et al. J Clin Lipidol Dec;12:390-396.e8; Ambry internal data). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Lo Surdo P et al. EMBO Rep., 2011 Dec;12:1300-5). In an assay testing LDLR function, this variant showed a functionally abnormal result (Graça R et al. JACC Basic Transl Sci, 2023 Aug;8:1010-1021). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Hypercholesterolemia Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;.;.;.;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H;.;.;.;.;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.7	D;D;D;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.77
MutPred		0.93		Loss of catalytic residue at A480 (P = 0.111);Loss of catalytic residue at A480 (P = 0.111);.;.;.;Loss of catalytic residue at A480 (P = 0.111);
MVP		1.0
MPC		0.89
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.97

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

Other links and lift over

dbSNP: rs144614838; hg19: chr19-11224284; COSMIC: COSV52941864; COSMIC: COSV52941864;