ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.1A>T (p.Met1Leu) (rs1131691049)

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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 RCV000492218 SCV000581194 pathogenic Hereditary cancer-predisposing syndrome 2014-03-25 criteria provided, single submitter clinical testing The p.M1L mutation (also known as c.1A>T) is located in exon 1 of the SDHB gene and results from an A to T substitution at nucleotide position 1. This changes the amino acid from methionine to leucine at the initiation codon. Since sequence variations that modify the initiation codon (ATG) are expected to cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med 2008;10:294).
Invitae RCV000692227 SCV000820039 likely pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2018-05-19 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 an individual affected with head and neck cancers (PMID: 23512077). ClinVar contains an entry for this variant (Variation ID: 428918). 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, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505307 SCV000599481 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

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