ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.314G>A (p.Trp105Ter)

dbSNP: rs1131691065
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492092 SCV000581228 pathogenic Hereditary cancer-predisposing syndrome 2019-02-14 criteria provided, single submitter clinical testing The p.W105* pathogenic mutation (also known as c.314G>A), located in coding exon 3 of the SDHD gene, results from a G to A substitution at nucleotide position 314. This changes the amino acid from a tryptophan to a stop codon within coding exon 3. This mutation was reported in a male diagnosed with two head/neck paragangliomas at age 20 and in a female diagnosed with one head/neck paraganglioma at age 13 (Fishbein L et al. Ann Surg Oncol. 2013 May;20(5):1444-50). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Invitae RCV002527068 SCV000946587 pathogenic Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas with sensorineural hearing loss; Cowden syndrome 3 2022-09-22 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SDHD protein in which other variant(s) (p.Gln121*) have been determined to be pathogenic (PMID: 12000816; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 428939). This premature translational stop signal has been observed in individual(s) with paragangliomas (PMID: 23512077). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp105*) in the SDHD gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 55 amino acid(s) of the SDHD protein.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV002291278 SCV002583775 pathogenic Mitochondrial complex 2 deficiency, nuclear type 3 2022-07-08 criteria provided, single submitter clinical testing PVS1 PM2 PS4_Supporting

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