16-2080365-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000548.5(TSC2):c.3598C>T(p.Arg1200Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,611,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1200P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:21O:2

Conservation

PhyloP100: 5.42

Variant links:

Genes affected

TSC2 (HGNC:12363): (TSC complex subunit 2) This gene is a tumor suppressor gene that encodes the growth inhibitory protein tuberin. Tuberin interacts with hamartin to form the TSC protein complex which functions in the control of cell growth. This TSC protein complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

TSC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-2080366-G-C is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

PP5

Variant 16-2080365-C-T is Pathogenic according to our data. Variant chr16-2080365-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 49770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2080365-C-T is described in Lovd as [Pathogenic]. Variant chr16-2080365-C-T is described in Lovd as [Pathogenic]. Variant chr16-2080365-C-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.3598C>T	p.Arg1200Trp	missense_variant	Exon 30 of 42	ENST00000219476.9	NP_000539.2	P49815-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9 link	c.3598C>T	p.Arg1200Trp	missense_variant	Exon 30 of 42	5	NM_000548.5	ENSP00000219476.3		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152204

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1459408

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725998

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

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:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tuberous sclerosis 2

Pathogenic:7Other:1

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1200 of the TSC2 protein (p.Arg1200Trp). This variant is present in population databases (rs45438205, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of TSC2-related conditions (PMID: 8824881, 9463313, 18792920, 21332470, 22867869, 25039834, 28149746). It has also been observed to segregate with disease in related individuals. This variant is also known as c.3616C>T (p.Arg1199Trp). ClinVar contains an entry for this variant (Variation ID: 49770). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TSC2 protein function. Experimental studies have shown that this missense change affects TSC2 function (PMID: 21309039, 21332470). For these reasons, this variant has been classified as Pathogenic. -

Feb 21, 2024

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21332470, 25039834, 32917966, 9463313, 32461669]. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 27406250, 21332470]. -

Jul 10, 2020

Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with tuberous sclerosis-2 (MIM#613254). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Clinical symptoms can be variable and subtle among affected individuals within the same family (PMIDs: 21332470, 31018109). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (both v2 and v3 listed 1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in many unrelated individuals with tuberous sclerosis complex, and is associated with the mild phenotype (mild skin lesions, remitting epilepsy, and absence of severe ID or major organ involvement) (PMIDs: 21332470, 30255984 and ClinVar). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies using HEK cells showed the variant restricted the TSC1-TSC2-dependent inhibition of TORC1 activity (PMID: 21332470). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.3598C>T (p.Arg1200Trp) in TSC2 gene has been reported in the literature to segregate with tuberous sclerosis complex and a wide range of phenotypes including some milder cases in many families(Wentink M et.al.,2012). Experimental studies have shown that this missense change results in an unstable protein and disrupts the normal function of TSC2 as a regulator of cellular growth and proliferation(Hoogeveen-Westerveld M et.al.,2011). This variant has been reported to the ClinVar database as Pathogenic. The p.Arg1200Trp variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes and allele frequency of 0.003187% is reported in gnomAD. The amino acid Arg at position 1200 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties.The amino acid change p.Arg1200Trp in TSC2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:7

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TSC2: PP1:Strong, PM5, PM6, PS4:Moderate, PM2:Supporting, PP3, PS3:Supporting -

May 20, 2014

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population, 0.000032 (1/31378 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in affected individuals with tuberous sclerosis, including de novo inheritance, and segregation with disease (PMIDs: 8824881 (1996), 9463313 (1998), 17304050 (2007), 18792920 (2008), 22867869 (2013), 25039834 (2014), 28149746 (2017), 32005694 (2020), and 32211034 (2020)). Functional studies found that this variant causes a deleterious effect to TSC2 protein function (PMIDs: 21309039 (2011) and 21332470 (2012)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -

Apr 14, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: destabilization of the TSC1-TSC2 complex and reduced inhibition of downstream targets (Hoogeveen-Westerveld et al., 2011; Wentink et al., 2012); While some individuals with this variant are reported to meet clinical diagnostic criteria for definite TSC, others have been reported to have a milder clinical presentation characterized primarily by the presence of skin findings with or without epilepsy (Wentink et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17304050, 18792920, 28149746, 20301399, 29655203, 21309039, 15798777, 11112665, 8824881, 9463313, 28178598, 22867869, 27406250, 29056246, 29308833, 31005478, 32917966, 32005694, 21332470, 32211034) -

Jul 21, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TSC2 c.3598C>T; p.Arg1200Trp variant (rs45438205) is reported in the literature in individuals and families affected with tuberous sclerosis (Altarescu 2008, Au 1998, van Eeghen 2013, Wentink 2012, Wilson 1996). This variant is also reported in ClinVar (Variation ID: 49770), but is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 1200 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.892). Additionally, functional assays demonstrate reduced complex formation and downstream signaling (Hoogeveen-Westerveld 2011, Wentink 2012). Based on available information, this variant is considered to be pathogenic. References: Altarescu et al. PGD on a recombinant allele: crossover between the TSC2 gene and 'linked' markers impairs accurate diagnosis. Prenat Diagn. 2008 Oct;28(10):929-33. Au et al. Germ-line mutational analysis of the TSC2 gene in 90 tuberous-sclerosis patients. Am J Hum Genet. 1998 Feb;62(2):286-94. Hoogeveen-Westerveld et al. Functional assessment of variants in the TSC1 and TSC2 genes identified in individuals with Tuberous Sclerosis Complex. Hum Mutat. 2011 Apr;32(4):424-35. van Eeghen et al. Central TSC2 missense mutations are associated with a reduced risk of infantile spasms. Epilepsy Res. 2013 Jan;103(1):83-7. Wentink et al. Functional characterization of the TSC2 c.3598C>T (p.R1200W) missense mutation that co-segregates with tuberous sclerosis complex in mildly affected kindreds. Clin Genet. 2012 May;81(5):453-61. Wilson et al. Novel mutations detected in the TSC2 gene from both sporadic and familial TSC patients. Hum Mol Genet. 1996 Feb;5(2):249-56. -

Jan 19, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PP3, PP4, PM5, PM6, PS3, PS4 -

May 20, 2014

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity. Found in multiple individuals with expected phenotype for this gene, including de novo cases. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease. -

Nov 20, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tuberous sclerosis syndrome

Pathogenic:3Other:1

Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Apr 25, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with tryptophan at codon 1200 of the TSC2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies with this variant have demonstrated that phosphorylation of S6 kinase was significantly increased compared to wild-type, indicating impairment of TSC1-TSC2 dependent inhibition of TORC1 activity (PMID: 21309039, 21332470). This variant has been reported in numerous individuals affected with tuberous sclerosis complex (TSC; PMID: 8824881, 9463313, 18792920, 21332470, 22867869, 25039834). This variant has also been observed to segregate with disease in multiple tuberous sclerosis families (PMID: 18792920, 21332470). This variant has been identified in 1/31378 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Mar 30, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg1200Trp variant in TSC2 (also described as p.Arg1199Trp in the literature) has been reported in >15 individuals with clinical features of tuberous sclerosis complex (TSC), including at least 1 de novo occurrence and segregated with TSC in >7 affected family members from multiple families and with clinical features of TSC in other families, suggesting a milder phenotype in these families (Wilson 1996 PMID: 8824881, Au 1998 PMID: 9463313, Altarescu 2008 PMID: 18792920, Wentik 2012 PMID: 21332470, van Eeghen 2013 PMID: 22867869, Jansen 2014 PMID: 25039834, Pannu 2017 PMID: 28149746, Ding 2020 PMID: 32211034). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 49770) and had been identified in 0.006% (1/15418) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that this variant may impact protein function (Wentik 2012 PMID: 21332470, Overwater 2016 PMID: 27406250) and computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant TSC. ACMG/AMP Criteria applied: PS4_Strong, PP1_Strong, PM6, PS3_Supporting, PP3. -

May 25, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TSC2 c.3598C>T (p.Arg1200Trp) 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 was absent in 247756 control chromosomes. c.3598C>T has been reported in the literature in multiple individuals affected with Tuberous Sclerosis Complex, including de novo inheritance, and in families where the variant was shown to segregate with disease (eg. Wilson_1996, Milunsky_2009, Wentink_2011, etc). Functional studies have shown the variant to inactivate the TSC1TSC2 complex, without preventing TSC1TSC2 binding (Wentink_2011). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2

Pathogenic:2

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PP3+PS3+PS4_Moderate+PP1_Strong -

Feb 01, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TSC2-related disorder

Pathogenic:1

Oct 25, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TSC2 c.3598C>T variant is predicted to result in the amino acid substitution p.Arg1200Trp. This variant has been reported in a large number of individuals and families with variable, often mild, manifestations of tuberous sclerosis complex (see for example, Wilson et al. 1996. PubMed ID: 8824881; Altarescu et al. 2008. PubMed ID: 18792920; Hoogeveen-Westerveld et al. 2011. PubMed ID: 21309039; Wentink et al. 2011. PubMed ID: 21332470; Butler et al. 2017. PubMed ID: 29056246). This variant is reported in 1 of ~31,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/16-2130366-C-T). It is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/49770/). This variant is interpreted as pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Sep 29, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1200W pathogenic mutation (also known as c.3598C>T), located in coding exon 29 of the TSC2 gene, results from a C to T substitution at nucleotide position 3598. The arginine at codon 1200 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been identified in numerous individuals with clinical features associated with tuberous sclerosis (Wilson PJ et al. Hum Mol Genet, 1996 Feb;5:249-56; Au KS et al. Genet Med, 2007; Feb;9:88-100 Yu T et al. Clin Neurol Neurosurg, 2017 Mar;154:104-108; Ambry internal data); however some carriers and families have been show to present with milder phenotype than classic TSC1/2 pathogenic mutations (Wentink M et al. Clin Genet, 2012 May;81:453-61; Jansen AC. Dev Med Child Neurol, 2014 Dec;56:1134-1135; van Eeghen AM et al. Epilepsy Res, 2013 Jan;103:83-7; Pannu et al. Respir Med Case Rep 2017 Jan;20:113-115). This variant was demonstrated to disrupt the function TSC1-TSC2 complex in in vitro functional studies (Hoogeveen-Westerveld M et al. Hum Mutat, 2011 Apr;32:424-35; Wentink M et al. Clin Genet, 2012 May;81:453-61) 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 available evidence, this alteration is classified as a pathogenic mutation associated with reduced penetrance compared to other TSC2 mutations. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

D;.;.;.;.;.;.;.;.;.;.;.;D;.;D

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.96

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.3

M;.;.;.;.;.;.;.;.;M;.;.;.;.;.

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-7.0

D;.;.;D;.;D;.;.;D;D;.;.;.;.;D

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;.;.;D;.;D;.;.;D;D;.;.;.;.;D

Sift4G

Pathogenic

0.0010

D;.;.;D;.;D;.;.;D;D;.;.;.;.;D

Polyphen

1.0

D;.;.;.;D;D;.;.;D;D;.;.;.;.;.

Vest4

0.98

MutPred

0.94

Gain of sheet (P = 0.039);.;Gain of sheet (P = 0.039);.;.;.;.;Gain of sheet (P = 0.039);.;Gain of sheet (P = 0.039);.;.;.;.;.;

MVP

0.99

ClinPred

1.0

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.79

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over