19-11102732-T-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS4PS3PP1_ModeratePM2PP3PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.259T>G (p.Trp87Gly) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS3, PS4, PP1_Moderate, 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: PS3 - Level 1/2 assays: PMID 31578082: Hmz patients' lymphocytes, FACS assays and Heterologous cells (CHO), WB, FACS and CLSM assays - results - lymphocytes: normal cell surface LDLR, 40% LDL-LDLR binding, 35% uptake; CHO: normal (100%) LDLR expression, 20% LDL-LDLR binding, 35% uptake ---- binding and uptake are below 70% of wild-type, so PS3 is Met.PS4 - Variant meets PM2. Variant identified in at least 13 unrelated index cases with Dutch Lipid Clinic score equal or above 6 from different labs.PP1_moderate - variant segregates with FH phenotype in 5 informative meiosis in 2 families from different labs.PM2 - PopMax MAF = 0.00005418 (0.0054%) in european non-finnish exomes (gnomAD v2.1.1).PP3 - REVEL = 0.892. PP4 - Variant meets PM2. Identified in 13 unrelated index cases with Dutch Lipid Clinic score equal or above 6 from different labs. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023683/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:29

Conservation

PhyloP100: 6.03

Publications

33 publications found

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]

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

LDLR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

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.

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 rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.259T>G	p.Trp87Gly	missense_variant	Exon 3 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.259T>G	p.Trp87Gly	missense_variant	Exon 3 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000278

AC:

AN:

251490

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000615

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461740

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000207

AC:

AN:

1111912

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41470

American (AMR)

AF:

0.0000656

AC:

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000259

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:29

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:17

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

- -

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:literature only

- -

Feb 04, 2020

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.259T>G (p.Trp87Gly) variant in the LDLR gene has been reported in multiple individuals with familial hypercholesterolemia (PMID: 2318961, 8054972, 8645371, 9259195, 9104431). It is located in the functionally important second LDLR type A repeat. Functional studies have demonstrated a deleterious effect of the p.Trp87Gly variant on LDL binding (PMID: 2318961, 8645371, 10735631). The variant is observed in gnomAD at a low minor allele frequency (8/282882). Multiple algorithms predicted this change to be deleterious. Therefore, the c.259T>G (p.Trp87Gly) variant in the LDLR gene is classified as pathogenic. -

Mar 13, 2019

Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Dec 16, 2016

Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

subjects mutated among 2600 FH index cases screened = 9 , family members = 7 with co-segregation / frequently associated with c.1975A>C, p.Thr659Pro (2 index cases), Subnormal LDLR activity / Software predictions: Damaging -

May 28, 2021

Johns Hopkins Genomics, Johns Hopkins University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant (rs121908025) is rare (<0.1%) in a large population database (gnomAD: 8/282882 total alleles, 0.003%, no homozygotes) and has an entry in ClinVar. It has been reported in multiple individuals with familial hypercholesterolemia-1, and is considered a founder mutation in the French-Canadian population. This variant is located in the second type A repeat of the ligand binding domain of the LDLR protein. Functional studies have demonstrated a deleterious effect of p.Trp87Gly on LDL binding and uptake. This variant was also identified in the patient's father, who has a personal history of elevated cholesterol. We consider c.259T>G to be pathogenic. -

Institute of Human Genetics Greifswald, Research Division, University Medicine Greifswald

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 14, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 20, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS4, PM2_Supporting, PP3, PM1, PS3_Moderate -

Jun 07, 2021

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000527.5(LDLR):c.259T>G (p.Trp87Gly) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS3, PS4, PP1_Moderate, 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: PS3 - Level 1/2 assays: PMID 31578082: Hmz patients' lymphocytes, FACS assays and Heterologous cells (CHO), WB, FACS and CLSM assays - results - lymphocytes: normal cell surface LDLR, 40% LDL-LDLR binding, 35% uptake; CHO: normal (100%) LDLR expression, 20% LDL-LDLR binding, 35% uptake ---- binding and uptake are below 70% of wild-type, so PS3 is Met. PS4 - Variant meets PM2. Variant identified in at least 13 unrelated index cases with Dutch Lipid Clinic score equal or above 6 from different labs. PP1_moderate - variant segregates with FH phenotype in 5 informative meiosis in 2 families from different labs. PM2 - PopMax MAF = 0.00005418 (0.0054%) in european non-finnish exomes (gnomAD v2.1.1). PP3 - REVEL = 0.892. PP4 - Variant meets PM2. Identified in 13 unrelated index cases with Dutch Lipid Clinic score equal or above 6 from different labs. -

Apr 01, 1994

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Sep 18, 2024

All of Us Research Program, National Institutes of Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.259T>G (p.Trp87Gly) variant, also known as p.Trp66Gly in LDLR gene that encodes for low density lipoprotein receptor, has been identified in numerous individuals (>100) affected with familial hypercholesterolemia (FH) (PMID:9104431, 2318961, 9259195, 9272705). This variant has also been reported in homozygous status in several individuals (>20) affected with severe FH (PMID: 8098448, 2318961, 9272705). This variant is considered as a founder mutation in the French-Canadian (PMID: 9272705) and Swedish population (PMID: 33955087). Experimental studies using patient derived lymphoblasts from true homozygotes revealed reduced LDLR binding and uptake (PMID: 31578082). Transfection of the mutant, p.Trp87Gly, protein in receptor deficient CHOldlA7 cells also showed significant reduction in LDL binding and uptake (PMID:31578082). Computational prediction tools suggest that the p.Trp87Gly variant may have deleterious effect on the protein function (REVEL score: 0.892). This variant is rare (24/1613912 chromosomes; 0.001487%) in the general population database, gnomAD v4.1.0 and interpreted as pathogenic by several submitters in the ClinVar database including the ClinGen variant curation expert panel (ClinVar ID: 3685). Therefore, the c.259T>G (p.Trp87Gly) variant in LDLR gene is classified as pathogenic. -

Dec 18, 2008

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

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Robarts Research Institute, Western University

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 06, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Criteria applied: PS3,PS4,PP1_MOD,PM2_SUP,PP3,PP4 -

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

- -

not provided

Pathogenic:5

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 07, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP3, PP4, PM2_supporting, PM3, PS3_supporting, PS4 -

Jan 24, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed frequently in heterozygous and homozygous states in unrelated patients from different ethnic backgrounds with FH in published literature (PMID: 2318961, 1301956, 8645371, 9259195, 9104431, 9272705, 9767373, 15528480, 16542394, 23669246, 24281370); Described as a French Canadian founder mutation and is a commonly identified variant in the European FH population (PMID: 9767373, 9272705, 16542394); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damanging effect as LDL receptor activity was significantly reduced in the fibroblasts from two of three unrelated individuals who were homozygous for the FH French Canadian-4 allele and this variant affects either LDLR turnover or the binding of the LDLR protein to LDL (PMID: 1301956, 2318961); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as FH French Canadian-4 and p.(W66G); This variant is associated with the following publications: (PMID: 28008010, 9104431, 2318961, 9259195, 8645371, 15528480, 23669246, 24281370, 9767373, 12381843, 30586733, 30512145, 29874871, 29261184, 31401775, 29407885, 31727422, 34040191, 32041611, 33303402, 32719484, 32770674, 33740630, 34037665, 33087929, 37589137, 37409534, 34363016, 33955087, 1301956, 9272705, 16542394) -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LDLR: PS4, PM2, PP1:Moderate, PP4, PS3:Supporting -

Jun 30, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial hypercholesterolemia

Pathogenic:4

Dec 14, 2020

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: LDLR c.259T>G (p.Trp87Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four 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 251490 control chromosomes. c.259T>G has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g. Leitersdorf_1990, Moorjani_1993, Banerjee_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, indicating the cells expressing the variant have reduced LDL-binding and uptake (e.g. Banerjee_2019). 11 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Feb 04, 2020

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 14, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces tryptophan with glycine at codon 87 in the second LDLR type A repeat of the ligand binding domain of the LDLR protein. This variant is also known as p.Trp66Gly in the mature protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Experimental functional studies have demonstrated that this variant causes reduced LDL binding, internalization and uptake (PMID: 8645371, 10735631, 31578082). This variant has been identified in over 500 individuals affected with familial hypercholesterolemia (PMID: 2318961, 8098448, 9104431, 9259195, 9272705, 9676383, 12553167, 15528480, 16542394, 23669246, 30512145, 31345425, 31578082, 33955087, 34037665, 37607748, 39407785). This variant is common in individuals of European descent and is considered a founder mutation in the French-Canadian population (PMID: 9272705) and Swedish population (PMID: 33955087). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 37607748; ClinVar SCV001960956.1). Homozygous individuals have been shown to carry significantly higher LDL-C levels than heterozygous individuals (PMID: 8098448, 36727130). This variant has been identified in 8/282882 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic. -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 87 of the LDLR protein (p.Trp87Gly). This variant is present in population databases (rs121908025, gnomAD 0.006%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 2318961, 12553167, 16542394). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of European ancestry (PMID: 2318961, 12553167, 16542394). 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.W66G. ClinVar contains an entry for this variant (Variation ID: 3685). 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%. Experimental studies have shown that this missense change affects LDLR function (PMID: 8098448). For these reasons, this variant has been classified as Pathogenic. -

Homozygous familial hypercholesterolemia

Pathogenic:1

Mar 29, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Trp87Gly variant in LDLR is a well-established pathogenic variant for familial hypercholesterolemia (Leitersdorf 1990, Jensen 1996, Vohl 1997, Tybjaerg-Hansen 2005, Futema 2013), and is a known founder mutation in the French Canadian population where it has been reported in >400 individuals with FH, including >15 homozygous individuals (Vohl 1997). It has also been identified in 5/66740 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs121908025); however, this frequency is low enough to be consistent with the frequency of FH in the general population. Additionally, in vitro functional studies provide some evidence that the p.Trp87Gly variant may impact protein function (Leitersdorf 1990). In summary, this variant meets our criteria to be classified as pathogenic for FH in an autosomal dominant manner based upon its identification in a large number of affected individuals and low frequency in controls. -

Dyslipidemia

Pathogenic:1

Jul 20, 2023

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Pathogenic:1

May 14, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.W87G pathogenic mutation (also known as c.259T>G), located in coding exon 3 of the LDLR gene, results from a T to G substitution at nucleotide position 259. The tryptophan at codon 87 is replaced by glycine, an amino acid with highly dissimilar properties. This mutation, historically reported as W66G, has been identified in multiple individuals with familial hypercholesterolemia (FH) (Leitersdorf E et al. J. Clin. Invest., 1990 Apr;85:1014-23; Brusgaard K et al. Clin. Genet., 2006 Mar;69:277-83; Langsted A et al. Lancet Diabetes Endocrinol, 2016 Jul;4:577-87). This alteration has been reported in FH patients across ethnic groups and has been designated a founder mutation in the French Canadian and Danish populations (Vohl MC et al. Clin. Genet., 1997 Jul;52:1-6; Jensen HK et al. Atherosclerosis, 1999 Oct;146:337-44). In vitro functional studies have demonstrated that this mutation causes defects in cell surface binding of LDL (Leitersdorf E et al. J. Clin. Invest., 1990 Apr;85:1014-23; Raungaard B et al. Clin. Genet., 2000 Feb;57:110-5). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.95

D;.;.;.;.

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

D;D;D;D;D

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

M;.;M;M;M

PhyloP100

6.0

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-12

D;D;D;D;D

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;D;T;D;D

Sift4G

Pathogenic

0.0

D;D;T;D;D

Polyphen

1.0

D;.;.;.;.

Vest4

0.81

MutPred

0.73

Loss of stability (P = 0.0576);Loss of stability (P = 0.0576);Loss of stability (P = 0.0576);Loss of stability (P = 0.0576);Loss of stability (P = 0.0576);

MVP

0.98

MPC

1.1

ClinPred

1.0

GERP RS

5.7

Varity_R

0.98

gMVP

0.98

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over