ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.315G>A (p.Trp105Ter) (rs1060503769)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000462080 SCV000554045 pathogenic Pheochromocytoma; Paragangliomas 1 2016-06-14 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the SDHD mRNA at codon 105 (p.Trp105*). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated SDHD protein. This variant is not present in population databases (ExAC no frequency). This particular variant has not been reported in the literature, but a different variant (c.314G>A) with the same protein effect (p.Trp105*) has been reported in an individual affected with pheochromocytomas (PCC) and paragangliomas (PGL) (PMID: 23512077). While no functional studies have been performed to test the effects of this particular variant on SDHD protein function or stability, it deletes 55 C-terminal amino acid residues from the SDHD protein. A founder mutation (p.Leu139Pro) has been reported in this region (PMID: 21348866, 11391798), and a downstream truncating variant has been classified as likely pathogenic in the Invitae database, indicating that the C-terminal amino acid residues may be critical for SDHD function. For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001386962 SCV001587412 pathogenic Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3 2016-06-14 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the SDHD mRNA at codon 105 (p.Trp105*). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated SDHD protein. This variant is not present in population databases (ExAC no frequency). This particular variant has not been reported in the literature, but a different variant (c.314G>A) with the same protein effect (p.Trp105*) has been reported in an individual affected with pheochromocytomas (PCC) and paragangliomas (PGL) (PMID: 23512077). While no functional studies have been performed to test the effects of this particular variant on SDHD protein function or stability, it deletes 55 C-terminal amino acid residues from the SDHD protein. A founder mutation (p.Leu139Pro) has been reported in this region (PMID: 21348866, 11391798), and a downstream truncating variant has been classified as likely pathogenic in the Invitae database, indicating that the C-terminal amino acid residues may be critical for SDHD function. For these reasons, this variant has been classified as Pathogenic. 1

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