1-17022648-C-T

Position:

chr1-17022648-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_003000.3(SDHB):c.725G>A(p.Arg242His) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,846 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R242C) has been classified as Likely pathogenic.

Frequency

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

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SDHB
NM_003000.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20

Conservation

PhyloP100: 5.63

Variant links:

Genes affected

SDHB (HGNC:10681): (succinate dehydrogenase complex iron sulfur subunit B) This tumor suppressor gene encodes the iron-sulfur protein subunit of the succinate dehydrogenase (SDH) enzyme complex which plays a critical role in mitochondria. The SDH enzyme complex is composed of four nuclear-encoded subunits. This enzyme complex converts succinate to fumarate which releases electrons as part of the citric acid cycle, and the enzyme complex additionally provides an attachment site for released electrons to be transferred to the oxidative phosphorylation pathway. The SDH enzyme complex plays a role in oxygen-related gene regulation through its conversion of succinate, which is an oxygen sensor that stabilizes the hypoxia-inducible factor 1 (HIF1) transcription factor. Sporadic and familial mutations in this gene result in paragangliomas, pheochromocytoma, and gastrointestinal stromal tumors, supporting a link between mitochondrial dysfunction and tumorigenesis. Mutations in this gene are also implicated in nuclear type 4 mitochondrial complex II deficiency. [provided by RefSeq, Jun 2022]

SDHB links:

SDHB (HGNC:):

SDHB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain in NM_003000.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-17022649-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 186827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 1-17022648-C-T is Pathogenic according to our data. Variant chr1-17022648-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17022648-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHB	NM_003000.3 linkuse as main transcript	c.725G>A	p.Arg242His	missense_variant	7/8	ENST00000375499.8	NP_002991.2	P21912
SDHB	NM_001407361.1 linkuse as main transcript	c.671G>A	p.Arg224His	missense_variant	7/8		NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8 linkuse as main transcript	c.725G>A	p.Arg242His	missense_variant	7/8	1	NM_003000.3	ENSP00000364649.3		P21912

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251440

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461722

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2023	Published functional studies demonstrate a damaging effect: significantly reduced SDH/complex II activity and abrogated SDHAF3 interaction (Kim et al., 2015; Nesti et al., 2015; Dwight et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); 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: 12213855, 19393419, 23433498, 25025441, 17102084, 29925701, 34906457, 32782288, 24606901, 22835832, 25736212, 12000816, 25972245, 21173220, 20208144, 22293219, 19258401, 17652212, 19802898, 22270996, 25047027, 19454582, 18551016, 28374168, 25899001, 27573198, 15328326, 24276837, 25873086, 19075037, 16317055, 28503760, 29386252, 29204718, 29951630, 29800631, 29950348, 28748451, 31212687, 30549360, 31104306, 30658386, 28490599, 31492822, 30050099, 26464466, 31589614, 32741965, 33644666, 30787465, 28738844) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 12, 2013	The frequency of this variant in the general population, 0.000012 (3/251440 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in multiple individuals affected with PGL-PCC syndrome (PMID: 12000816 (2002), 12213855 (2002), 18551016 (2008), 19351833 (2009), 29386252 (2018), 34439168 (2021), 34906457 (2022)). Functional studies observed decreased stability of the SDHB protein (PMID: 22835832 (2012)) and a severe decrease in succinate dehydrogenase activity (PMID: 25736212 (2015), 25972245 (2015)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 02, 2023	The SDHB c.725G>A; p.Arg242His variant (rs74315368) is reported in the literature in individuals affected with paraganglioma or pheochromocytoma (Luiz 2013, Neumann 2002, Neumann 2009, Niemeijer 2017, Young 2002). In at least one family, this variant was observed to segregate with disease (Young 2002). This variant is also reported in ClinVar (Variation ID: 12781). It is only found on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.944). Consistent with these predictions, functional assays have observed that this variant exhibits decreased SDH/complex II activity (Kim 2015, Nesti 2015) and increased ubiquitination (Yang 2012). Additionally, other amino acid substitutions at this codon (p.Arg242Cys, p.Arg242Ser) have been reported in individuals with paraganglioma and are considered pathogenic (Badenhop 2004, Neumann 2009). Based on available information, the p.Arg242His variant is considered to be pathogenic. References: Badenhop RF et al. The prevalence of SDHB, SDHC, and SDHD mutations in patients with head and neck paraganglioma and association of mutations with clinical features. J Med Genet. 2004 Jul;41(7):e99. PMID: 15235042. Kim E et al. Structural and functional consequences of succinate dehydrogenase subunit B mutations. Endocr Relat Cancer. 2015 Jun;22(3):387-97. PMID: 25972245. Luiz HV et al. Malignant paraganglioma presenting with hemorrhagic stroke in a child. Pediatrics. 2013 Dec;132(6):e1709-14. PMID: 24276837. Nesti C et al. Additive effect of nuclear and mitochondrial mutations in a patient with mitochondrial encephalomyopathy. Hum Mol Genet. 2015 Jun 1;24(11):3248-56. PMID: 25736212. Neumann HP et al. Clinical predictors for germline mutations in head and neck paraganglioma patients: cost reduction strategy in genetic diagnostic process as fall-out. Cancer Res. 2009 Apr 15;69(8):3650-6. PMID: 19351833. Neumann HP et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002 May 9;346(19):1459-66. PMID: 12000816. Niemeijer ND et al. The phenotype of SDHB germline mutation carriers: a nationwide study. Eur J Endocrinol. 2017 Aug;177(2):115-125. PMID: 28490599. Yang C et al. Missense mutations in the human SDHB gene increase protein degradation without altering intrinsic enzymatic function. FASEB J. 2012 Nov;26(11):4506-16. PMID: 22835832. Young AL et al. Familial malignant catecholamine-secreting paraganglioma with prolonged survival associated with mutation in the succinate dehydrogenase B gene. J Clin Endocrinol Metab. 2002 Sep;87(9):4101-5. PMID: 12213855. -

Paragangliomas 4

Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 04, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Oct 05, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 08, 2024	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 30050099, 32462735, 33362715, 34439168]. This variant is expected to disrupt protein structure [Myriad internal data]. -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Apr 17, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PP3. -

Hereditary pheochromocytoma-paraganglioma

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 27, 2023	Variant summary: SDHB c.725G>A (p.Arg242His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251440 control chromosomes. c.725G>A has been reported in the literature in multiple individuals affected with features of Hereditary Paraganglioma-Pheochromocytoma Syndrome (example, Persu_2008, Amar_2007, Young_2002, Benn_2006, Neumann_2004, Neumann_2002). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 12000816, 17652212, 16317055, 15328326, 18551016, 12213855). Ten 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. -
Pathogenic, no assertion criteria provided	research	Section on Medical Neuroendocrinolgy, National Institutes of Health	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 08, 2024	The c.725G>A variant in the SDHB gene is located on the exon 7 and is predicted to replace arginine with histidine at codon 242 (p.Arg242His). The variant has been reported in multiple unrelated individuals with paraganglioma/pheochromocytoma/renal cell carcinoma (PMID: 12000816, 32661476, 33748650, 36597280, 29925701, 33362715, 34906457). Alternative variants disrupting the same amino acid (p.Arg242Ser, p.Arg242Cys) have been interpreted as pathogenic (ClinVar ID: 239443, 186827). In vitro SDH activity assay and co-immunoprecipitation experiment in mammalian cells demonstrated impaired function and abolished interaction with the SDH aseembly factor SDHAF3 (PMID: 25972245, 28738844). The variant is reported in ClinVar (ID: 12781). The variant is rare in general population according to gnomAD (18/1613846 chromosomes, 0.001%) . Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.94). Therefore, the c.725G>A (p.Arg242His) variant in the SDHB gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Nov 10, 2020	The SDHB c.725G>A variant is a single nucleotide substitution from a guanine to an adenonine at position 725 which is predicted to change the arginine at position 242 in the protein to histidine. The variant has been reported multiple times in the literature in association with disease (PMID: 12000816, 12213855, 15328326, 28490599) (PS1). Functional studies demonstrate that the variant has a detrimental effect on protein function (PMID: 25972245, 22835832) (PS3). The variant is listed in dbSNP (rs74315368) and is rare in population databases (gnomAD 3 het/251,440 total, 0 hom). The variant is described in ClinVar as pathogenic (ClinVar ID: 27820) and HGMD (2020.3) as disease causing (PP5). Computational predictions support a deleterious effect on the gene or gene product. -

Gastrointestinal stromal tumor

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 04, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 20, 2021	- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 08, 2022	The p.R242H pathogenic mutation (also known as c.725G>A), located in coding exon 7 of the SDHB gene, results from a G to A substitution at nucleotide position 725. The arginine at codon 242 is replaced by histidine, an amino acid with highly similar properties. The p.R242H mutation has been well described in published literature. It has been identified in numerous individuals with tumors across the paraganglioma-pheochromocytoma (PGL-PCC) syndrome spectrum, including thoracic, pelvic, and head and neck PGL, adrenal PCC, and renal cell carcinoma (Neumann HP et al. JAMA. 2004 Aug;292:943-51; Ghayee HK et al. Endocr. Relat. Cancer. 2009 Mar;16:291-9; Luiz HV et al. Pediatrics. 2013 Dec;32:e1709-14; Persu A et al. J. Hypertens. 2008 Jul;26:1395-401; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug;94:2817-27; Merlo A et al. J. Clin. Endocrinol. Metab 2013 Oct;98:E1661-6; Rattenberry E et al. J. Clin. Endocrinol. Metab. 2013 Jul;98:E1248-56; van Hulsteijn LT et al. Fam. Cancer. 2014 Dec;13:651-7; Janssen I et al. Clin. Cancer Res. 2015 Sep;21:3888-95; Gill AJ et al. Am. J. Surg. Pathol. 2014 Dec;38:1588-602). In one study, mutant yeast strains with this mutation showed a significant defect and structural analysis suggested that this mutation alters the conformation of the protein, causing a decrease in the positive surface extent of the mutant protein (Nesti C et al. Hum. Mol. Genet. 2015 Jun;24:3248-56). Additionally, structural modeling of this mutation has predicted disruption of the electron path and impaired functional activity (Kim E et al. Endocr. Relat. Cancer. 2015 Jun;22:387-97). Of note, two different alterations at the same codon, p.R242C and p.R242S, have also been reported in patients with head/neck PGLs and PCCs (Panizza E et al. Hum. Mol. Genet. 2013 Feb;22:804-15; Neumann HP et al. Cancer Res. 2009 Apr;69:3650-6; Lefebvre S et al. Horm. Metab. Res. 2012 May;44:334-8; Badenhop RF et al. J. Med. Genet. 2004 Jul;41:e99). Based on the available evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jul 06, 2021	- -

Mitochondrial complex 2 deficiency, nuclear type 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Feb 02, 2022

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 mitochondrial complex II deficiency, nuclear type 4 (MIM#619224), pheochromocytoma (MIM#171300) and paragangliomas 4 (MIM#115310). (I) 0108 - This gene is associated with both recessive and dominant disease. However, the genotype-phenotype correlation is currently unestablished (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (GeneReviews). I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated 4Fe-4S dicluster domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in several individuals with pheochromocytoma (MIM#171300) and/or paragangliomas 4 (MIM#115310), rarely in non-paraganglioma tumours such as gastrointestinal stromal tumour and a single case of mitochondrial encephalomyopathy (PMID: 32460727, 33748650, 28490599, 21173220, 25736212). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 242 of the SDHB protein (p.Arg242His). This variant is present in population databases (rs74315368, gnomAD 0.007%). This missense change has been observed in individuals with sporadic and familial hereditary paragangliomas and/or pheochromocytomas (PMID: 12000816, 12213855, 17102084, 20208144, 21173220, 22270996, 24276837, 25736212). ClinVar contains an entry for this variant (Variation ID: 12781). 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 SDHB protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SDHB function (PMID: 22835832, 25736212, 25972245). This variant disrupts the p.Arg242 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). 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. -

SDHB-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Feb 14, 2022

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 25972245; 25736212; 22835832) - PS3. The c.725G>A;p.(Arg242His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 12781; OMIM: 185470.0004; PMID: 12000816; 20208144; 24276837; 12213855; 17102084; 22270996) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Fer4) - PM1. This variant is not present in population databases (rs7431536, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 239443 - c.724C>A (p.Arg242Ser); ClinVar ID: 186827 - c.724C>T (p.Arg242Cys)) - PM5. Missense variant in SDHB that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. In summary, the currently available evidence indicates that the variant is pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-4.0

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.93

MutPred

0.94

Loss of MoRF binding (P = 0.0969);

MVP

0.99

MPC

0.78

ClinPred

1.0

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.78

gMVP

0.89

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