rs875989907

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM5_StrongPS4PM2PP3PP1PP4PS3_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c. c.796G>A (p.Asp266Asn) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4, PM2, PM5_Strong, PS3_Moderate, PP1, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PS4 - Variant meets PM2. Variant identified in 10 unrelated index cases (1 case fulfilling Simon-Broome criteria published in PMID:12414836; 1 case probably fulfilling Simon-Broome criteria published in PMID:12417285; 1 case with DLCN criteria from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 4 cases with Simon-Broome criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 3 cases with DLCN criteria from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory);PM2 - PopMax MAF = 0.00006533 (0.006533%) in South Asian exomes (gnomAD v2.1.1);PM5_Strong - 4 other missense variants in the same codon: - NM_000527.5(LDLR): c.796G>T (p.Asp266Tyr) (ClinVar ID 251456) - Pathogenic by these guidelines. - NM_000527.5(LDLR): c.797A>T (p.Asp266Val) (ClinVar ID 251458) - Likely Pathogenic by these guidelines. - NM_001195803.2(LDLR):c.797A>G (p.Asp266Gly) (ClinVar ID 251457) - Likely pathogenic by these guidelines. - NM_001195803.2(LDLR): c.798T>A (p.Asp266Glu) - (ClinVar ID 161287) - Pathogenic by these guidelines.There are 2 variants in the same codon classified as Pathogenic by these guidelines.PS3_Moderate - Level 2 assay: PMID 12414836: Homozygous patient cells, 125I assays - result - <2% LDL-LDLR binding and internalisation. Functional study is consistent with damaging effect;PP1 - 3 informative meioses identified by Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation);PP3 - REVEL = 0,83;PP4 - Variant meets PM2. Identified in at least 1 FH case fulfilling Simon-Broome criteria published in PMID 12414836. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10576288/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:19

Conservation

PhyloP100: 9.99

Publications

15 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 15 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.

PM5

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.796G>A	p.Asp266Asn	missense_variant	Exon 5 of 18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.796G>A	p.Asp266Asn	missense_variant	Exon 5 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

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:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251478

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:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111988

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

152186

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15262

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:

4836

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:12

Aug 07, 2024

All of Us Research Program, National Institutes of Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.796G>A (p.Asp266Asn) variant (also known as p.Asp245Asn) in the LDLR gene that encodes for low density lipoprotein receptor, has been identified in multiple unrelated individuals (>10) who fulfill the clinical criteria of familial hypercholesterolemia and segregated with disease in multiple families (PMID:11810272, 23375686, 15199436, 12417285, 19446849, 14974088). Experimental studies using homozygous patient derived cells revealed less than 2% LDLR activity compared to wild type (PMID: 12414836). In-silico computational prediction tools suggest that the p.Asp266Asn variant may have deleterious effect on the protein function (REVEL score: 0.832). This variant is rare (3/251478; 0.00001193) in the general population database, gnomAD. This variant is classified as pathogenic by multiple submitters in the ClinVar database including the ClinGen Variant Curation Expert Panel (ClinVar ID: 226334). Other missense variants affecting the same amino acid, p.Asp266Glu and p.Asp266Tyr, are classified as pathogenic by multiple ClinVar submitters including the ClinGen Variant Curation Expert Panel (ClinVar ID: 251456, 161287). Therefore, the c.796G>A (p.Asp266Asn) variant in the LDLR gene is classified as pathogenic. -

May 04, 2022

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000527.5(LDLR):c. c.796G>A (p.Asp266Asn) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4, PM2, PM5_Strong, PS3_Moderate, PP1, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PS4 - Variant meets PM2. Variant identified in 10 unrelated index cases (1 case fulfilling Simon-Broome criteria published in PMID: 12414836; 1 case probably fulfilling Simon-Broome criteria published in PMID: 12417285; 1 case with DLCN criteria from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 4 cases with Simon-Broome criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 3 cases with DLCN criteria from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory); PM2 - PopMax MAF = 0.00006533 (0.006533%) in South Asian exomes (gnomAD v2.1.1); PM5_Strong - 4 other missense variants in the same codon: - NM_000527.5(LDLR): c.796G>T (p.Asp266Tyr) (ClinVar ID 251456) - Pathogenic by these guidelines. - NM_000527.5(LDLR): c.797A>T (p.Asp266Val) (ClinVar ID 251458) - Likely Pathogenic by these guidelines. - NM_001195803.2(LDLR):c.797A>G (p.Asp266Gly) (ClinVar ID 251457) - Likely pathogenic by these guidelines. - NM_001195803.2(LDLR): c.798T>A (p.Asp266Glu) - (ClinVar ID 161287) - Pathogenic by these guidelines. There are 2 variants in the same codon classified as Pathogenic by these guidelines. PS3_Moderate - Level 2 assay: PMID 12414836: Homozygous patient cells, 125I assays - result - <2% LDL-LDLR binding and internalisation. Functional study is consistent with damaging effect; PP1 - 3 informative meioses identified by Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); PP3 - REVEL = 0,83; PP4 - Variant meets PM2. Identified in at least 1 FH case fulfilling Simon-Broome criteria published in PMID 12414836. -

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance:Pathogenic

Review Status:no assertion criteria provided

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

subject mutated among 2600 FH index cases screened = 1 , family members = 2 with co-segregation / previously described in association with FH / Software predictions: Damaging -

Sep 19, 2017

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This c.796G>A (p.Asp266Asn) variant in the LDLR gene has been reported in multiple patients with familial hypercholesterolemia (PMID: 11810272, 23375686). Multiple different amino acid substitutions affecting aspartic acid at position 266 of the LDLR protein have also been reported in patients with familial hypercholesterolemia (PMID: 1301956, 12417285, 28235710). The c.796G>A variant is extremely rare in the general population and aspartic acid at position 266 of the LDLR protein is highly evolutionarily conserved. The c.796G>A (p.Asp266Asn) variant in the LDLR gene is classified as likely pathogenic. -

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

The p.Asp266Asn (sometimes called p.Asp245Asn) variant in LDLR has been reported in at least 15 individuals (including 8 Norwegian, 3 Tunisian, 1 Dutch, 1 Japanese, and 1 German individuals) with Hypercholesterolemia, segregated with disease in 11 affected relatives from 3 families (PMID: 12414836, 11810272, 15199436, 12417285, 19446849, 14974088), and has been identified in 0.006533% (2/30616) of South Asian chromosomes and 0.005437% (1/18394) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs875989907). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic and pathogenic in ClinVar (Variation ID: 226334). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional variant with a different amino acid change at the same position (p.Asp266Glu) has been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 161287). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM5_supporting, PS4_Moderate, PP1_Moderate, PP3 (Richards 2015). -

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

- -

Dec 15, 2021

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

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

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:literature only

- -

Jan 05, 2022

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The LDLR p.Asp266Asn (originally p.Asp245Asn) missense variant occurs within the ligand-binding domain of the LDL-receptor and is pathogenic for familial hypercholesterolaemia (FH). In silico algorithms (PolyPhen2, SIFT, MutationTaster) predict LDLR p.Asp266Asn to be pathogenic. It, along with different missense variants at the same codon (p.Asp266Glu, p.Asp266Gly, p.Asp266Tyr, p.Asp266Val), has previously been identified in multiple cohorts of FH patients worldwide. Studies in cultured patient cells showed that LDL-receptor activity in the homozygous state is <2% of normal (PMID:12414836). -

Familial hypercholesterolemia

Pathogenic:3

Aug 28, 2023

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 05, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces aspartic acid with asparagine at codon 266 in the LDLR type A repeat 6 of the LDLR protein. This variant is also known as p.Asp245Asn in the mature protein, and FH Tozeur in the literature. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. A functional study using fibroblasts derived from a homozygous carrier individual have shown that this variant causes a significant reduction in LDL-R activity (PMID: 12414836). This LDLR variant has been reported in over 20 heterozygous individuals affected with familial hypercholesterolemia (PMID: 11810272, 12414836, 12417285, 14974088, 15199436, 15823288, 19446849, 22698793, 23375686, 26020417, 30312929, 33740630, 34037665; ClinVar SCV002568103.1). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in an individual affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 34834584). It has been shown that this variant segregates with disease in multiple affected individuals from multiple families (PMID: 12414836, 22417841; ClinVar SCV002568103.1). This variant has been identified in 3/251478 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon (p.Asp266Glu, p.Asp266Gly, p.Asp266Val, p.Asp266His, p.Asp266Tyr) are considered to be disease-causing (ClinVar variation ID: 161287, 251457, 251458, 1761428, 251456), suggesting that aspartic acid at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. -

Feb 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 266 of the LDLR protein (p.Asp266Asn). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 14974088, 22417841, 22698793, 23375686). This variant is also known as p.Asp245Asn. ClinVar contains an entry for this variant (Variation ID: 226334). 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.Asp266 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 11196104, 20663204, 21310417, 22698793, 23375686, 26238499). 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. -

Homozygous familial hypercholesterolemia

Pathogenic:1

Apr 16, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Asp266Asn variant in LDLR has been reported in the heterozygous state in 3 individuals with familial hypercholesterolemia (FH), in the homozygous state in 1 individual with a more severe presentation and segregated with disease in 2 affected individuals from 2 families (Fouchier 2001, Slimani 2012, Tichy 2012, Bertolini 2013). It has also been reported by other clinical laboratories in ClinVar (Variation ID 161287) and has identified in 3/251478 pan-ethnic chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of FH in the general population. Computational prediction tools and conservation analysis suggest that this variant may impact the protein. In addition, another variant involving this codon (p.Asp266Glu) has been identified in individuals with FH and is classified as pathogenic by this laboratory. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant FH. ACMG/AMP criteria applied: PM2, PM5, PP3, PS4_Supporting. -

Dyslipidemia

Pathogenic:1

Aug 08, 2024

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS4, PM5_strong, PS3_mod, PM2, PP1, PP3, PP4 -

not provided

Pathogenic:1

Mar 06, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in many unrelated individuals with familial hypercholesterolemia in published literature (PMID: 11810272, 12417285, 14974088, 15199436, 15823288, 19446849, 21310417, 22698793, 23375686, 31491741); Observed in apparent homozygous state and in compound heterozygous state in several patients with severe clinical presentations of FH in the published literature, and not observed in homozygous state in controls (PMID: 22417841, 12414836, 31386798, 32977124); Not observed at significant frequency in large population cohorts (gnomAD); Disrupts a negatively charged triplet, Ser-Asp-Glu, located at the carboxyl-terminal end of the LDL-receptor class A6 repeat domain that is critical for ligand binding (PMID: 12827279); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as FH-Tozeur and p.(D245N); This variant is associated with the following publications: (PMID: 34037665, 30241732, 32331935, 23375686, 31447099, 31491741, 33740630, 11810272, 32977124, 12414836, 31386798, 15199436, 14974088, 19446849, 21310417, 22698793, 15823288, 22417841, 37728764, 35913489, 35480308, 33955087, 12417285, 12827279) -

Cardiovascular phenotype

Pathogenic:1

Apr 23, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.D266N pathogenic mutation (also known as c.796G>A), located in coding exon 5 of the LDLR gene, results from a G to A substitution at nucleotide position 796. The aspartic acid at codon 266 is replaced by asparagine, an amino acid with highly similar properties. This variant (also referred to as D245N) was reported in individual(s) with features consistent with familial hypercholesterolemia and segregated with disease in at least one family (Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15; Yu W et al. Atherosclerosis, 2002 Dec;165:335-42; Slimane MN et al. J. Med. Genet., 2002 Nov;39:e74; Dedoussis GV et al. Hum. Mutat., 2004 Mar;23:285-6; Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Damgaard D et al. Atherosclerosis, 2005 May;180:155-60; Guardamagna O et al. J. Pediatr., 2009 Aug;155:199-204.e2; Du&scaron;ková L et al. Atherosclerosis, 2011 May;216:139-45). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

D;.;.;.;.

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D;D;D;D

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

1.0

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.0

H;.;.;.;H

PhyloP100

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-4.6

D;D;D;D;D

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0010

D;D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D;D

Polyphen

1.0

D;.;.;.;.

Vest4

0.85

MutPred

0.94

Loss of disorder (P = 0.1784);Loss of disorder (P = 0.1784);.;.;Loss of disorder (P = 0.1784);

MVP

1.0

MPC

0.79

ClinPred

1.0

GERP RS

5.1

Varity_R

0.99

gMVP

0.99

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over