ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.3G>C (p.Met1Ile) (rs80338842)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492533 SCV000581230 pathogenic Hereditary cancer-predisposing syndrome 2016-08-11 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). 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.
Invitae RCV000791414 SCV000645371 pathogenic Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3 2020-08-22 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the SDHD mRNA. An alternate in-frame methionine downstream of the initiator codon is located at codon 91, which could potentially rescue translational initiation. This variant is not present in population databases (rs80338842, ExAC no frequency). This variant has been observed in individuals and families affected with head and neck paragangliomas (HNPGLs) (PMID: 11391796, 21792967, 21945342, 12782822). In addition, different changes at the initiator codon (c.1A>G, c.2T>A, and c.2T>C) have also been observed in individuals and families with HNPGLs or non-HNPGLs, and have been shown to segregate with disease in the affected families (PMID: 15066320, 21945342, 19454582, 19351833, 17576205, 22241717). ClinVar contains an entry for this variant (Variation ID: 6906). While this variant is expected to result in an absent protein product, possible rescue of translational initiation by the downstream methionine would lead to the loss of ~60% of the SDHD protein, which contains the signal peptide domain required for entering into mitochondria (PMID: 12612654, 15066320). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000020522 SCV000967764 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes 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.
OMIM RCV000007315 SCV000027512 pathogenic Paragangliomas 1 2001-07-01 no assertion criteria provided literature only
GeneReviews RCV000020522 SCV000040979 pathologic Hereditary Paraganglioma-Pheochromocytoma Syndromes 2012-08-30 no assertion criteria provided curation Converted during submission to Pathogenic.

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