ClinVar Miner

Submissions for variant NM_003001.5(SDHC):c.1A>T (p.Met1Leu)

dbSNP: rs755235380
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000809572 SCV000949727 pathogenic Gastrointestinal stromal tumor; Paragangliomas 3 2024-04-28 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the SDHC mRNA. The next in-frame methionine is located at codon 38. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with SDHC-related conditions (PMID: 11062460, 16249420, 19351833, 19454582, 22351710, 22517554, 23282968, 29386252). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 653751). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc. RCV004028671 SCV004933709 pathogenic Paragangliomas 3 2023-12-12 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 30201732, 30877234, 16249420, 11062460, 25720320].
Ambry Genetics RCV004669129 SCV005161244 pathogenic Hereditary cancer-predisposing syndrome 2024-05-21 criteria provided, single submitter clinical testing The p.M1? pathogenic mutation (also known as c.1A>T) is located in coding exon 1 of the SDHC gene and results from an A to T substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This variant was reported in multiple individuals with features consistent with SDHC-related paraganglioma-pheochromocytoma syndrome (Andrews KA et al. J Med Genet, 2018 Jun;55:384-394; Williams et al. Clin Endocrinol (Oxf), 2022 Apr;96:499-512). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

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