Submissions for variant NM_003000.3(SDHB):c.481del (p.Asp161fs)

dbSNP: rs794728949

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183220	SCV000235640	pathogenic	not provided	2018-07-10	criteria provided, single submitter	clinical testing	The c.481delG variant causes a shift in the reading frame starting with codon Aspartic acid 161, changes this amino acid to a Methionine residue, and creating a premature Stop codon at position 14 of the new reading frame, denoted p.Asp161MetfsX14. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Although this pathogenic variant has not been previously reported in a peer-reviewed journal to our knowledge, its presence is consistent with a diagnosis of Hereditary Paraganglioma-Pheochromocytoma Syndrome (PGL/PCC). The variant is found in the SDHB panel(s).
Ambry Genetics	RCV000492455	SCV000581198	pathogenic	Hereditary cancer-predisposing syndrome	2024-10-09	criteria provided, single submitter	clinical testing	The c.481delG pathogenic mutation, located in coding exon 5 of the SDHB gene, results from a deletion of one nucleotide at nucleotide position 481, causing a translational frameshift with a predicted alternate stop codon (p.D161Mfs*14). This mutation has been reported in a patient with PGL/PCC whose tumor demonstrated loss of SDHB staining by immunohistochemistry (Evenepoel L et al. Genet Med, 2015 Aug;17:610-20). This mutation was also reported in a patient with carotid body tumor at age 25 (McCrary HC et al. JAMA Otolaryngol Head Neck Surg, 2019 07;145:641-646). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000183220	SCV000886097	pathogenic	not provided	2018-04-01	criteria provided, single submitter	clinical testing	The SDHB c.481delG; p.Asp161fs variant (rs794728949) is reported in the literature in an individual with abdominal paraganglioma (van Nederveen 2009). This variant is also reported as pathogenic in ClinVar (Variation ID: 201606), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database). This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES van Nederveen FH et al. An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. Lancet Oncol. 2009 Aug;10(8):764-71.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003765132	SCV004588897	pathogenic	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2022-12-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp161Metfs*14) 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 variant has not been reported in the literature in individuals affected with SDHB-related conditions. ClinVar contains an entry for this variant (Variation ID: 201606). For these reasons, this variant has been classified as Pathogenic.