Submissions for variant NM_003000.3(SDHB):c.311delinsGG (p.Asn104fs)

dbSNP: rs786201316

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163361	SCV000213898	pathogenic	Hereditary cancer-predisposing syndrome	2025-03-14	criteria provided, single submitter	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 variant was reported in individual(s) with features consistent with SDHB-related paraganglioma-pheochromocytoma syndrome (Benn DE et al. J Clin Endocrinol Metab. 2006;91(3):827-36; 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000801474	SCV000941251	pathogenic	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2025-01-12	criteria provided, single submitter	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.
Revvity Omics, Revvity	RCV001781508	SCV002020045	pathogenic	not provided	2021-09-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528907	SCV004108969	pathogenic	SDHB-related disorder	2023-05-04	criteria provided, single submitter	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.
All of Us Research Program, National Institutes of Health	RCV003995250	SCV004821942	pathogenic	Hereditary pheochromocytoma-paraganglioma	2023-11-02	criteria provided, single submitter	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/).
Myriad Genetics, Inc.	RCV004019957	SCV004930788	pathogenic	Paragangliomas 4	2024-02-08	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
GeneDx	RCV001781508	SCV005687901	pathogenic	not provided	2024-08-01	criteria provided, single submitter	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)