Submissions for variant NM_003002.4(SDHD):c.3G>C (p.Met1Ile)

dbSNP: rs80338842

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000492533	SCV000581230	pathogenic	Hereditary cancer-predisposing syndrome	2024-09-26	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002228007	SCV000645371	pathogenic	Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas with sensorineural hearing loss; Cowden syndrome 3	2024-06-30	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the SDHD mRNA. The next in-frame methionine is located at codon 91. This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 6906). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000020522	SCV000967764	pathogenic	Hereditary pheochromocytoma-paraganglioma	2019-07-21	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV005414445	SCV006081670	pathogenic	not provided	2024-11-26	criteria provided, single submitter	clinical testing	Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21945342, 31365623, 31447099, 34309460, 22241717, 19258401, 36722519, 15066320, 21792967, 17406045, 30093976, 33308260, 12782822, 29777207, 17576205, 11391796, 26096992, 19454582, 19351833)
OMIM	RCV000007315	SCV000027512	pathogenic	Paragangliomas 1	2001-07-01	no assertion criteria provided	literature only
GeneReviews	RCV000020522	SCV000040979	not provided	Hereditary pheochromocytoma-paraganglioma		no assertion provided	literature only