chr1-17053947-C-A

Position:

• chr1-17053947-C-A

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PM2 PP3_Strong PP5_Very_Strong

The NM_003000.3(SDHB):​c.72+1G>T variant causes a splice donor change. The variant allele was found at a frequency of 0.0000158 in 1,459,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: SDHB NM_003000.3 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 3.92

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]

ACMG classification

Verdict is Pathogenic. Variant got 22 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-17053947-C-A is Pathogenic according to our data. Variant chr1-17053947-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 142764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17053947-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHB	NM_003000.3	c.72+1G>T		splice_donor_variant		ENST00000375499.8
SDHB	NM_001407361.1	c.72+1G>T		splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHB	ENST00000375499.8	c.72+1G>T		splice_donor_variant		1	NM_003000.3	P1
SDHB	ENST00000466613.2	n.84+1G>T		splice_donor_variant, non_coding_transcript_variant		2
SDHB	ENST00000485515.5	n.60+1G>T		splice_donor_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000124 AC: 3 AN: 242838 Hom.: 0 AF XY: 0.0000151 AC XY: 2 AN XY: 132056

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000276

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1459768 Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11 AN XY: 726122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 15, 2022	Canonical splice site variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26916530, 19215943, 21934479, 16912137, 16472267, 19864450, 29204718, 23666964, 25741136, 20418362, 20459544, 18419787, 17200167, 24623741, 16317055, 17667967, 19522823, 28973655, 28374168, 27910947, 26556299, 29909963, 30694796, 29623478, 28748451, 30050099, 31492822, 32581362, 29386252, 33087929, 32741965, 30787465) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 22, 2014	The SDHB c.72+1G>T variant (also known IVS1+1G>T) disrupts a canonical splice-donor site and interferes with normal SDHB mRNA splicing. The frequency of this variant in the general population, 0.000028 (3/108524 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, this variant has been shown to cause aberrant splicing in patient RNA (PMID: 17667967 (2008)), and reported in multiple individuals with PGL-PCC (PMIDs: 33362715 (2020), 31492822 (2020), 30201732 (2018), 16912137 (2006), 16317055 (2006)), gastrointestinal stromal tumor (PMIDs: 17667967 (2008), 17804857 (2007)), and renal cell carcinoma (PMIDs: 35441217 (2022), 26556299 (2016), 20459544 (2010)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 10, 2013	- -

Hereditary pheochromocytoma-paraganglioma Pathogenic:3

Pathogenic, no assertion criteria provided	research	Section on Medical Neuroendocrinolgy, National Institutes of Health	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 27, 2021	Variant summary: SDHB c.72+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5` splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing and indicated that the first part of intron 1 was transcribed with the frameshift resulting in a stop codon in the middle of exon 2, predicting a truncated protein (Pasini_2007). The variant allele was found at a frequency of 1.2e-05 in 242838 control chromosomes (gnomAD). c.72+1G>T has been reported in the literature in multiple individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome (Pasini_2007, Benn_2018, Richter_2019, Dwight_2021). These data indicate that the variant is very likely to be associated with disease. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=5) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jun 10, 2021	The SDHB c.72+1G>T intronic change results in a G to T substitution at the +1 position of intron 1 of the SDHB gene. This variant is predicted to result in loss of the native splice donor site and abnormal gene splicing, resulting in nonsense-mediated decay or an abnormal protein product (PVS1). This variant has a maximum subpopulation frequency of 0.0028% in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/variant/1-17380442-C-A?dataset=gnomad_r2_1). This variant has been reported in individuals with pheochromocytoma (PMID: 16317055, 18419787, 23666964, 31492822), paraganglioma (PMID: 16472267, 16912137, 20418362, 29909963, 30050099), gastrointestinal stromal tumor (PMID: 17804857), and renal cell carcinoma (PMID: 20459544, 26556299). This variant is also known as IVS1+1G>T in the literature. In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria: PVS1, PS4, PM2_Supporting. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 22, 2021	The c.72+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 1 of the SDHB gene. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with SDHB-related disease (Ambry internal data; Benn DE et al. J Clin Endocrinol Metab. 2006: 91(3); 827-836; Brouwers FM et al. J Endocrinol Metab. 2006;91(11):4505-9; Timmers HJ et al. J Clin Endocrinol Metab. 2007;92(3): 779-86; Tsang VH et al. Endocr Relat Cancer. 2014 May 6;21(3):415-26; Jochmanova I et al. J. Cancer Res. Clin. Oncol. 2017 Aug;143(8):1421-1435; Pasini B et al. Eur J Hum Genet 2008 Jan;16(1):79-88; McWhinney SR et al. N Engl J Med 2007 Sep;357(10):1054-6; Rattenberry E et al. J Clin Endocrinol Metab 2013 Jul;98(7):E1248-56; Elston MS et al. Intern Med J 2006 Feb;36(2):129-31). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	research	Academic Department of Medical Genetics, University of Cambridge	Jan 26, 2018	Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 10, 2019

The SDHB c.72+1G>T variant (rs587782703) is reported in the literature in individuals affected with pheochromocytoma (Benn 2006, Timmers 2007, Tsang 2014), paraganglioma (Brouwers 2006), gastrointestinal tumor (Pasini 2008, McWhinney 2008), and renal cell carcinoma (Schrader 2016). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 142764), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant disrupts the canonical splice donor site of intron 1, which is likely to negatively impact gene function, and functional analyses of patient mRNA shows aberrant splicing (Pasini 2008). Additionally, other variants at this nucleotide (c.72+1G>A, c.72+1G>C) have been reported in individuals with pheochromocytoma or paraganglioma and are considered pathogenic (Burnichon 2009, Ricketts 2010). Based on available information, the c.72+1G>T variant is considered to be pathogenic. References: Benn DE et al. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J Clin Endocrinol Metab. 2006 Mar;91(3):827-36. Brouwers FM et al. High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing. J Clin Endocrinol Metab. 2006 Nov;91(11):4505-9. Burnichon N et al. The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. J Clin Endocrinol Metab. 2009 Aug;94(8):2817-27. McWhinney SR et al. Familial gastrointestinal stromal tumors and germ-line mutations. N Engl J Med. 2007 Sep 6;357(10):1054-6. Pasini B et al. Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur J Hum Genet. 2008 Jan;16(1):79-88. Ricketts CJ et al. Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. Hum Mutat. 2010 Jan;31(1):41-51. Schrader KA et al. Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA. JAMA Oncol. 2016 Jan;2(1):104-11. Timmers HJ et al. Clinical presentations, biochemical phenotypes, and genotype-phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas. J Clin Endocrinol Metab. 2007 Mar;92(3):779-86. Tsang VH et al. Overexpression of miR-210 is associated with SDH-related pheochromocytomas, paragangliomas, and gastrointestinal stromal tumours. Endocr Relat Cancer. 2014 May 6;21(3):415-26. -

Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

This sequence change affects a donor splice site in intron 1 of the SDHB gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individuals with clinical features of SDHB-related conditions (PMID: 16317055, 16472267, 16912137, 17667967, 18419787, 20418362, 20459544, 23666964). This variant is also known as IVS1+1G>T. ClinVar contains an entry for this variant (Variation ID: 142764). Studies have shown that disruption of this splice site results in retention of part of intron 1 and introduces a premature termination codon (PMID: 17667967; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Paragangliomas 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jan 30, 2023

This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 23512077, 33362715, 30201732, 28374168]. -

Gastrointestinal stromal tumor Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 27, 2023

- -

Carney-Stratakis syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Benign	0.70	D
MutationTaster	Benign	1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.85
RBP_regulation_power_radar		4.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.34		Position offset: 2
DS_DL_spliceai		1.0		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs587782703; hg19: chr1-17380442;