ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.3G>A (p.Met1Ile) (rs1131691061)

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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 RCV000492186 SCV000581214 pathogenic Hereditary cancer-predisposing syndrome 2017-08-24 criteria provided, single submitter clinical testing The p.M1? variant (also known as c.3G>A), located in coding exon 1 of the SDHB gene, results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon. This alteration has been detected in multiple individuals with paraganglioma and/or pheochromocytoma (Neumann HP et al. Cancer Res. 2009 Apr;69(8):3650-6; Piccini V et al. Endocr. Relat. Cancer 2012 Apr;19(2):149-55; Sjursen W et al. Fam. Cancer 2013 Sep;12(3):529-35; Papathomas TG et al. Eur. J. Endocrinol. 2014 Jan;170:1-12). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000550393 SCV000644758 likely pathogenic Paragangliomas 4 2017-03-27 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the SDHB mRNA. The next in-frame methionine is located at codon 58. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with paragangliomas, pheochromocytomas and renal cell carcinomas (PMID: 19351833, 23407919, 24096523, 27279923, 22241717). This variant is expected to result in an absent or disrupted protein product. If translation initiation is rescued by the downstream methionine at codon 58, this would result in loss of the mitochondrial targeting sequence (residues 1-28), and partially affect Fe-S binding domain (residues 40-133) of the SDHB protein (PMID: 23083876). A missense change (p.Arg46Gln) within the N-terminal region has been determined to be pathogenic (PMID: 12618761, 14500403, 15328326, 16314641, 17102082, 18362451, 23083876, 23282968), suggesting that this variant is expected to disrupt SDHB protein function. In summary, this variant is a rare initiator codon variant that has been observed in affected individuals, and is expected to disrupt an important protein domain. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Invitae RCV001379744 SCV001577603 likely pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2017-03-10 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the SDHB mRNA. The next in-frame methionine is located at codon 58. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with paragangliomas, pheochromocytomas and renal cell carcinomas (PMID: 19351833, 23407919, 24096523, 27279923, 22241717). This variant is expected to result in an absent or disrupted protein product. If translation initiation is rescued by the downstream methionine at codon 58, this would result in loss of the mitochondrial targeting sequence (residues 1-28), and partially affect Fe-S binding domain (residues 40-133) of the SDHB protein (PMID: 23083876). A missense change (p.Arg46Gln) within the N-terminal region has been determined to be pathogenic (PMID: 12618761, 14500403, 15328326, 16314641, 17102082, 18362451, 23083876, 23282968), suggesting that this variant is expected to disrupt SDHB protein function. In summary, this variant is a rare initiator codon variant that has been observed in affected individuals, and is expected to disrupt an important protein domain. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 3

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