chr1-17028712-T-CC

Position:

• chr1-17028712-T-CC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_003000.3(SDHB):​c.311delinsGG​(p.Asn104ArgfsTer15) variant causes a frameshift 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 (★★). Synonymous variant affecting the same amino acid position (i.e. N104N) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SDHB NM_003000.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• 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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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/exons	MANE	UniProt
SDHB	NM_003000.3	c.311delinsGG	p.Asn104ArgfsTer15	frameshift_variant	4/8	ENST00000375499.8
SDHB	NM_001407361.1	c.311delinsGG	p.Asn104ArgfsTer15	frameshift_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHB	ENST00000375499.8	c.311delinsGG	p.Asn104ArgfsTer15	frameshift_variant	4/8	1	NM_003000.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Sep 23, 2021

- -

Paragangliomas 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Feb 08, 2024

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

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 18, 2019

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

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 04, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Nov 02, 2023

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;