rs786201316

Variant names:

• chr1-17028712-T-CC
• rs786201316
• NM_003000.3:c.311delAinsGG

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PS1 PM2 PP5_Very_Strong

The NM_003000.3(SDHB):​c.311delAinsGG​(p.Asn104ArgfsTer15) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N104K) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SDHB NM_003000.3 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.33

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: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS1: Transcript NM_003000.3 (SDHB) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-17028712-T-CC is Pathogenic according to our data. Variant chr1-17028712-T-CC is described in ClinVar as [Pathogenic]. Clinvar id is 184177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHB	NM_003000.3	c.311delAinsGG	p.Asn104ArgfsTer15	frameshift_variant, missense_variant	Exon 4 of 8	ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1	c.311delAinsGG	p.Asn104ArgfsTer15	frameshift_variant, missense_variant	Exon 4 of 8		NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.311delAinsGG	p.Asn104ArgfsTer15	frameshift_variant, missense_variant	Exon 4 of 8	1	NM_003000.3	ENSP00000364649.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Aug 01, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift 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 significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect: impaired enzymatic activity (PMID: 25972245); This variant is associated with the following publications: (PMID: 36786389, 16317055, 19215943, 26273102, 31492822, 30694796, 30201732, 29386252, 25972245) -

Sep 23, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Asn104Argfs*15) in the SDHB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHB are known to be pathogenic (PMID: 19454582, 19802898). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with pheochromocytoma and paraganglioma (PMID: 16317055, 25972245, 31492822). This variant is also known as c.311delAinsGG. For these reasons, this variant has been classified as Pathogenic. -

Paragangliomas 4 Pathogenic:1

Feb 08, 2024

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 18, 2019

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.311delAinsGG pathogenic mutation, located in coding exon 4 of the SDHB gene, results from the deletion of one nucleotide and insertion of two nucleotides at position 311, causing a translational frameshift with a predicted alternate stop codon (p.N104Rfs*15). This mutation has been described in a patient with a history of pheochromocytoma and head and neck paraganglioma (Benn DE et al. J Clin Endocrinol Metab. 2006;91(3):827-36). It was also identified in two related patients who were diagnosed with paraganglimoas in adolescence (Tufton N et al. Endocr Connect. 2019 Mar;8(3):162-172). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

SDHB-related disorder Pathogenic:1

May 04, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SDHB c.311delinsGG variant is predicted to result in a frameshift and premature protein termination (p.Asn104Argfs*15). This variant has been reported in an individuals with pheochromocytoma and/or paraganglioma (Table 1, Benn et al. 2006. PubMed ID: 16317055; Table 1, Tufton et al. 2019. PubMed ID: 30694796). In vitro experimental studies indicate this variant impacts protein function (Figure 2, Kim et al. 2015. PubMed ID: 25972245). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/184177/). Frameshift variants in SDHB are expected to be pathogenic. This variant is interpreted as pathogenic. -

Hereditary pheochromocytoma-paraganglioma Pathogenic:1

Nov 02, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is predicted to result in loss of protein function through nonsense-mediated decay or protein truncation. Loss of function is an established mechanism of disease. This prediction has not been confirmed by functional studies. This variant has been reported in multiple individuals with phaeochromocytoma and paraganglioma (PMID: 36786389, 30201732, 29386252, 26273102, 25972245, 16317055). This variant is present in 1/251424 total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs786201316; hg19: chr1-17355207;