Submissions for variant NM_004168.4(SDHA):c.667del (p.Asp223fs)

dbSNP: rs587782077

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130573	SCV000185445	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-06	criteria provided, single submitter	clinical testing	The c.667delG pathogenic mutation, located in coding exon 6 of the SDHA gene, results from a deletion of one nucleotide at nucleotide position 667, causing a translational frameshift with a predicted alternate stop codon (p.D223Ifs*3). This variant has been reported in a Dutch patient diagnosed with bilateral glomus vagal tumors and a glomus carotid body tumor at age 49 (van der Tuin K et al. J Clin Endocrinol Metab, 2018 02;103:438-445). This nucleotide position is highly conserved in available vertebrate species. 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.
Invitae	RCV000527052	SCV000651338	pathogenic	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp223Ilefs*3) in the SDHA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHA are known to be pathogenic (PMID: 22974104, 24781757). This variant is present in population databases (rs779126007, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with a carotid body tumor and bilateral glomus vagal tumors (PMID: 29177515). ClinVar contains an entry for this variant (Variation ID: 141876). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001008075	SCV001167813	pathogenic	not provided	2023-04-04	criteria provided, single submitter	clinical testing	Observed in the heterozygous state in an individual with epilepsy, although a second variant in SDHA was not identified (Hesse et al., 2018); 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; This variant is associated with the following publications: (PMID: 28152038, 29778030, 31589614, 29177515)
Sema4, Sema4	RCV000130573	SCV002527761	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-11-25	criteria provided, single submitter	curation
Baylor Genetics	RCV003474765	SCV004202369	pathogenic	Dilated cardiomyopathy 1GG	2023-10-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001008075	SCV004220314	pathogenic	not provided	2022-08-28	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the SDHA mRNA and causes the premature termination of SDHA protein synthesis. The frequency of this variant in the general population, 0.00017 (6/35438 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in an individual with paragangliomas (PMID: 29177515 (2018)). Based on the available information, this variant is classified as pathogenic.