19-11105588-G-T

Variant summary

Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PP1_ModeratePM2PVS1PP4PS3PS4

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.682G>T (p.Glu228Ter) variant is classified as pathogenic for Familial Hypercholesterolemia by applying evidence code PVS1, PS3, PS4, PM2, PP1_Moderate 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: PM2 - PopMax MAF = 0.00006530 (0.006%) in African/African American exomes (gnomAD v2.1.1). PVS1 - Variant leads to stop at codon 228, amino-terminal of amino acid 830. PS3 - Two studies contribute to PS3 attribution. One (PMID:1301956) report a level 2 assay performed on homozygous patient's fibroblasts with radiolabeled LDL consistent with damaging effect of the variant (< 2% LDLR activity). The second reports a level 1 assay (PMID:17087781) performed on Heterologous cells (COS7). FACS, CLSM and WB results in <5% LDLR activity. LDLR precursor protein does not mature. PS4 - Variant meets PM2 and is identified in 22 index cases who fulfil SB criteria for FH (n=2 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière) or DLCN criteria for FH (n=4 Color Health, Inc.; n=14 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière; n=2 Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA)) PP1_Moderate - Variant segregate with FH in 3 informatives meiosis (LDL-C > 75th percentile) and not segregate with variant in 1 relative with LDL-C <25th percentile from at least 1 family from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA). PP4 - Variant meets PM2 and is identified in 22 index cases who fulfil SB criteria for FH (n=2 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière) or DLCN criteria for FH (n=4 Color Health, Inc.; n=14 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière; n=2 Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA)) LINK:https://erepo.genome.network/evrepo/ui/classification/CA044327/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

LDLR
NM_000527.5 stop_gained

Scores

5
1
1

Clinical Significance

Pathogenic reviewed by expert panel P:27

Conservation

PhyloP100: 9.88
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 21 ACMG points.

PVS1
For more information check the summary or visit ClinGen Evidence Repository.
PS3
For more information check the summary or visit ClinGen Evidence Repository.
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.
PP4
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LDLRNM_000527.5 linkuse as main transcriptc.682G>T p.Glu228Ter stop_gained 4/18 ENST00000558518.6 NP_000518.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LDLRENST00000558518.6 linkuse as main transcriptc.682G>T p.Glu228Ter stop_gained 4/181 NM_000527.5 ENSP00000454071 P3P01130-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152184
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000943
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000807
AC:
2
AN:
247898
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135086
show subpopulations
Gnomad AFR exome
AF:
0.0000653
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000893
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000756
AC:
11
AN:
1454752
Hom.:
0
Cov.:
34
AF XY:
0.00000969
AC XY:
7
AN XY:
722400
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000993
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152184
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74340
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000943
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:27
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:15
Pathogenic, reviewed by expert panelcurationClinGen Familial Hypercholesterolemia Variant Curation Expert PanelApr 30, 2022NM_000527.5(LDLR):c.682G>T (p.Glu228Ter) variant is classified as pathogenic for Familial Hypercholesterolemia by applying evidence code PVS1, PS3, PS4, PM2, PP1_Moderate 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: PM2 - PopMax MAF = 0.00006530 (0.006%) in African/African American exomes (gnomAD v2.1.1). PVS1 - Variant leads to stop at codon 228, amino-terminal of amino acid 830. PS3 - Two studies contribute to PS3 attribution. One (PMID: 1301956) report a level 2 assay performed on homozygous patient's fibroblasts with radiolabeled LDL consistent with damaging effect of the variant (< 2% LDLR activity). The second reports a level 1 assay (PMID: 17087781) performed on Heterologous cells (COS7). FACS, CLSM and WB results in <5% LDLR activity. LDLR precursor protein does not mature. PS4 - Variant meets PM2 and is identified in 22 index cases who fulfil SB criteria for FH (n=2 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière) or DLCN criteria for FH (n=4 Color Health, Inc.; n=14 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière; n=2 Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA)) PP1_Moderate - Variant segregate with FH in 3 informatives meiosis (LDL-C > 75th percentile) and not segregate with variant in 1 relative with LDL-C <25th percentile from at least 1 family from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA). PP4 - Variant meets PM2 and is identified in 22 index cases who fulfil SB criteria for FH (n=2 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière) or DLCN criteria for FH (n=4 Color Health, Inc.; n=14 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière; n=2 Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA)) -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityJul 18, 2023- -
Pathogenic, criteria provided, single submitterclinical testingHuman Genome Sequencing Center Clinical Lab, Baylor College of MedicineDec 31, 2019The c.682G>T variant in exon 4 of the LDLR gene introduces a premature translation termination codon (p.Glu228Ter). It is expected to result in protein truncation or an absent protein product via nonsense mediated decay. This variant has been observed in multiple unrelated patients with familial hypercholesterolemia (PMID: 23375686, 9974426, 26343872, 7649546, 1301956). Other loss-of-function variants in LDLR are known to be pathogenic and associated with FH (PMID: 26482752). This variant is present at low frequency in the gnomAD population database (3/279288 alleles). We consider the c.682G>T (p.Glu228Ter) variant in LDLR to be pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthJan 05, 2024The c.682G>T (p.Glu228*) variant in the LDLR gene is located on the exon 4 and introduce a premature translation termination codon (p.Glu228*), resulting in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 23375686, 33418990, 26748104). The variant has been identified in more than 10 unrelated individuals with familial hypercholesterolemia (FH) (PMID: 26748104, 27680772, 33418990, 28502495, 34363016, 25962062). The variant segregates with FH phenotype in 3 informative meiosis in a family according to the ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel. Experimental study with the homozygous patient cells (<2% LDLR activity) and heterologous cultured cells (<5% LDLR activity) proved the defective LDLR activity and negative functional impact of this variant (PMID: 1301956, 17087781). The variant has been reported in ClinVar as pathogenic (ID: 226333) and reviewed by the expert panel. The variant is rare in general population according to gnomAD (3/279288). Therefore, the c.682G>T (p.Glu228*) variant of LDLR has been classified as pathogenic. -
Pathogenic, criteria provided, single submittercuration;literature onlyCardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo JorgeMar 01, 2016- -
Pathogenic, criteria provided, single submitterliterature onlyLDLR-LOVD, British Heart FoundationMar 25, 2016- -
Pathogenic, no assertion criteria providedclinical testingCardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley HospitalAug 11, 2011- -
Pathogenic, criteria provided, single submitterclinical testingDepartment of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und KollegenOct 09, 2018The mutation leads to a premature stop codon at protein level at position 228 (position 207 of the mature protein). This change has already been described in the literature as FH Morocco allele and is associated with elevated cholesterol and LDL-C levels. PMID: 1131376, 7649546, 7903864 -
Pathogenic, criteria provided, single submitterresearchBrunham Lab, Centre for Heart and Lung Innovation, University of British ColumbiaMay 23, 2019- -
Likely pathogenic, criteria provided, single submitterclinical testingRobarts Research Institute, Western University-- -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsSep 10, 2021- -
Pathogenic, criteria provided, single submitterclinical testingU4M - Lille University & CHRU Lille, Université de Lille - CHRU de LilleMar 30, 2017- -
Pathogenic, no assertion criteria providedresearchLaboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum-- -
Pathogenic, criteria provided, single submitterclinical testingCentre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-FoixDec 16, 2016subjects mutated among 2600 FH index cases screened = 7 , family member = 1 with co-segregation / FH-Morocco, 2% LDLR Activity -
Pathogenic, criteria provided, single submitterresearchHudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for BiotechnologyMar 20, 2019ACMG codes: PVS1, PS3, PS4, PP5 -
not provided Pathogenic:6
Pathogenic, criteria provided, single submitterclinical testingAiLife Diagnostics, AiLife DiagnosticsJan 25, 2022- -
Pathogenic, no assertion criteria providedprovider interpretationStanford Center for Inherited Cardiovascular Disease, Stanford UniversityNov 16, 2017p.Glu228* (c.682G>T) in exon 4 of the LDLR gene (NM_000527.4; chr19-11216264-G-T) SCICD Classification: pathogenic variant based on strong case data. We do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: LDLR: LDL receptors are located on the surface of the liver and play an important role in LDL recycling. Pathogenic variants in LDLR account for 80% of cases of familial hypercholesterolemia. Both missense and truncating/frameshift variants can be pathogenic. Truncating variants in LDLR are a known mechanism of disease (Marduel et al 2010). Exon 4 in LDLR encodes a binding domain for both apoB and apoE. Case data (not including our patient): at least 12. ClinVar: LDLR-LOVD, British Heart Foundation, University of Western Ontario, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix (7 unrelated cases and segregated with disease in 1 family member), Lille University, Cardiovascular Research Group, Istituto Nacional de Saude Doutor Ricardo Jorge, Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum, Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital - all likely pathogenic or pathogenic. Cases in the literature: At least 12. Note: this variant is also known as p.Glu207* in the literature. Hobbs et al 1992: this variant caused less than 2% LDLR activity. The patient was Moroccan American. Nauck et al 2001: This variant was found in 5 patients with FH. Kim et al 2004: Found in 2 of 25 unrelated Korean patients with FH. Taylor et al 2010: Detected this variant in 1 of 20 patients with definite FH. Dušková et al 2011: detected in 1 of 1945 unrelated Czech patients with FH. Futema et al 2012: 2 of 48 patients with FH (British descent). Segregation data: none reported Functional data: Truncating variants in LDLR are a known mechanism of disease (Marduel et al 2010). Exon 4 in LDLR encodes a binding domain for both apoB and apoE (Hobbs et al 1992). Conservation data: The glutamic acid at codon 228 is completely conserved across species. Amino acid at position 227 is also completely conserved. Nearby pathogenic variants at this codon or neighboring codons: Many nearby truncating variants near this codon. Population data: Highest MAF in African population: 0.0066%. The variant was reported online in 2 of 122,195 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 1 of 7,543 individuals of African descent (MAF=0.0066%) and 1 of 55,223 individuals of European descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). -
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoApr 24, 2023The LDLR c.682G>T (p.Glu228*) variant causes the premature termination of LDLR protein synthesis. This variant has been reported in the published literature as FH Morocco or E207X in multiple individuals and families affected with hypercholesterolemia (PMIDs: 7903864 (1994), 10735632 (2000), 33740630 (2021), 34363016 (2021), 34456200 (2021)). Functional studies have shown that this variant produces no protein that results in the loss of LDLR functional activity (PMIDs: 1301956 (1992), 9409298 (1997), 17087781 (2006)). The frequency of this variant in the general population, 0.000011 (3/279288 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicMay 23, 2022PS3_moderate, PS4, PVS1 -
Pathogenic, criteria provided, single submitterclinical testingAthena DiagnosticsJun 27, 2013- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxNov 09, 2021Also known as p.E207* and FH Morocco; Not observed at significant frequency in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate loss of normal protein function by nonsense-mediated mRNA decay (Charng et al., 2006) and, consequently, results in minimal LDL receptor activity (<2%) (Hobbs et al., 1992); Reported in ClinVar (ClinVar Variant ID# 226333; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26343872, 23375686, 10735632, 7903864, 9409298, 7649546, 15199436, 17094996, 11462246, 25525159, 32220565, 1301956, 28502495, 17087781, 30512145, 30592178, 30586733, 30333156, 30526649, 31102204, 31447099, 32719484, 33740630, 34037665, 33087929, 15359125) -
Familial hypercholesterolemia Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024This sequence change creates a premature translational stop signal (p.Glu228*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is present in population databases (rs121908029, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 1301956, 11462246, 15359125, 19843101, 21310417, 23054246). This variant is also known as p.Glu207*. ClinVar contains an entry for this variant (Variation ID: 226333). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Oct 14, 2020- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 21, 2016Variant summary: The LDLR c.682G>T (p.Glu228X) variant (alternatively also known as E207X) results in a premature termination codon, predicted to cause a truncated or absent LDLR protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. Functional analyses show that this variant results into NMD causing absent LDLR protein (Charng_2006) and/or extremely low LDL receptor activity (Hobbs_1992). Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Cys276X, p.Val295fsX75). This variant is widely reported in FH patients and is a recurrent pathogenic mutation (Hobbs_1992, Leren_2004, Muller_2004, Charng_2006, Humphries_2006). This variant was found in 2/117006 control chromosomes at a frequency of 0.0000171, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0025031). The heterozygotes in ExAC are likely to represent as subclinical cases or reduced penetrance. Multiple clinical lab/research centers have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJan 18, 2023This variant changes 1 nucleotide in exon 4 of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over 15 individuals and affected with familial hypercholesterolemia (PMID: 1301956, 11462246, 15359125, 23054246, 28008010). This variant has been identified in 3/279288 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic. -
Homozygous familial hypercholesterolemia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 03, 2019The p.Glu228X variant in LDLR (also described as p.Glu207X in the literature) has been reported in 23 individuals with familial hypercholesterolemia (FH; Hobbs 1992, Nauck 2001, Bodamer 2002, Kim 2004, Taylor 2007, Hola 2009, Vandrovcova 2013, Han 2015, Du 2016, Abul-Husn 2016) and segregated with disease in 6 affected relatives from 3 families (Bodamer 2002, Kim 2004). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 226333). In vitro functional studies provide some evidence that the p.Glu228X variant may impact protein function (Hobbs 1992, Holla 2009). This variant has also been identified in 1/23818 African and 2/125438 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs12190829). This frequency is low enough to be consistent with the frequency of FH in the general population. This nonsense variant leads to a premature termination codon at position 228, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in individuals with FH. In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dominant manner based upon presence in multiple affected individuals, segregation studies, low frequency in the general population, predicted impact on the protein, and functional evidence. The ACMG/AMP criteria applied (Richards 2015): PVS1; PM2; PS4; PP1_Moderate; PS3_Supporting. -
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJun 04, 2021The p.E228* pathogenic mutation (also known as c.682G>T), located in coding exon 4 of the LDLR gene, results from a G to T substitution at nucleotide position 682. This changes the amino acid from a glutamic acid to a stop codon within coding exon 4. This alteration, also reported as p.E207*, has been identified in numerous individuals with familial hypercholesterolemia from a variety of ethnic groups (Hobbs HH et al. Hum Mutat, 1992;1:445-66; Lombardi MP et al. Clin Genet, 2000 Feb;57:116-24; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Shin DG et al. Atherosclerosis, 2015 Nov;243:53-8; Cao YX et al. J Transl Med, 2018 12;16:345; Chan ML et al. Mol Genet Genomic Med, 2019 02;7:e00520). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.63
CADD
Pathogenic
40
DANN
Uncertain
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.97
FATHMM_MKL
Pathogenic
1.0
D
MutationTaster
Benign
1.0
A;A;A;A;A;D;D
Vest4
0.90
GERP RS
5.6

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs121908029; hg19: chr19-11216264; API