ClinVar Genomic variation as it relates to human health

The c.3G>C (p.Met1?) variant in SDHD has been identified to be a Chinese founder variant and has been reported in at least 13 Chinese individuals with hereditary paragangliomas and/or pheochromocytomas (PGL/PCC), segregating with disease in at least 10 relatives in these families (Badenhop 2001, Lee 2003, Ma 2007, Zha 2011, Wang 2012, Zhu 2015). This variant has also been reported by other clinical laboratories in Clinvar (Variation ID: 6906) and was absent from large population studies. The p.Met1? variant alters the evolutionary conserved initiation codon of the SDHD gene and is predicted to disrupt translation. The precise effect on the protein cannot be predicted, as this variant may lead to no protein synthesis or the activation of an upstream translation initiation codon, resulting in an aberrant protein. Additionally, other variants at this position, resulting in the same impact on the protein, have been reported in individuals with PGL/PCC (Burnichon 2009, Cascon 2009, Neumayer 2007, Piccini 2012, Riemann 2004). Heterozygous loss of function of the SDHD gene is an established disease mechanism in individuals with hereditary PGL/PCC. In summary, this variant meets criteria to be classified as pathogenic for hereditary PGL/PCC in an autosomal dominant manner based upon multiple occurrences in affected individuals, segregation studies, absence from the general population, and the predicted impact on protein. ACMG/AMP criteria applied: PS4; PVS1_Moderate, PM2, PP1_Strong.

Disruption of the initiator codon has been observed in individual(s) with clinical features of SDHD-related conditions (PMID: 11391796, 12782822, 15066320, 17576205, 19351833, 19454582, 21792967, 21945342, 22241717). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 6906). 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.

The p.M1? pathogenic mutation (also known as c.3G>C) is located in coding exon 1 of the SDHD gene and results from a G to C substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. This mutation has been reported in multiple Asian families affected with early onset paragangliomas, and haplotype analysis has identified it as a Chinese founder mutation (Badenhop RF et al. Genes Chromosomes Cancer. 2001 Jul;31(3):255-63; Lee SC et al. Laryngoscope, 2003 Jun;113:1055-8; Ma RC et al. Hong Kong Med J, 2007 Apr;13:151-4; Zha Y et al. Laryngoscope. 2011 Aug;121(8); Wang CP et al. Oral Oncol. 2012 Feb;48(2):125-9; Ting KR et al. Hered Cancer Clin Pract 2020 Dec;18(1):24). This alteration is also denoted as p.M1I throughout the literature. 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.