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

Total submissions: 5

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	Other acmg-defined mutation (i.e. initiation codon or gross deletion);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Good segregation with disease (lod 1.5-3 = 5-9 meioses)
Invitae	RCV000791414	SCV000645371	pathogenic	Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3	2019-12-04	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.