ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.1A>G (p.Met1Val)

dbSNP: rs104894307
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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 RCV002228010 SCV000554046 pathogenic Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas with sensorineural hearing loss; Cowden syndrome 3 2022-02-17 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 6911). Disruption of the initiator codon has been observed in individuals with head and neck paragangliomas (HNPGLs) or non-HNPGLs (PMID: 11391796, 15066320, 17576205, 19351833, 19454582, 21945342, 22241717). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the SDHD mRNA. The next in-frame methionine is located at codon 91.
Ambry Genetics RCV004948132 SCV005500701 pathogenic Hereditary cancer-predisposing syndrome 2024-09-05 criteria provided, single submitter clinical testing The p.M1? pathogenic mutation (also known as c.1A>G) is located in coding exon 1 of the SDHD gene and results from a A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). Alterations affecting the initiation codon of SDHD have been observed in individuals with hereditary paraganglioma and pheochromocytoma syndrome (Ambry internal data; Lee SC et al. Laryngoscope, 2003 Jun;113:1055-8; Wang CP et al. Oral Oncol. 2012 Feb;48(2):125-9; Neumayer C et al. Eur J Clin Invest 2007 Jul;37(7):544-51;). 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.
OMIM RCV004018582 SCV000027518 pathogenic Paragangliomas 1 2004-04-15 no assertion criteria provided literature only

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