Submissions for variant NM_003002.4(SDHD):c.242C>T (p.Pro81Leu) (rs80338844)

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162448	SCV000212801	pathogenic	Hereditary cancer-predisposing syndrome	2018-10-09	criteria provided, single submitter	clinical testing	The p.P81L pathogenic mutation (also known as c.242C>T), located in coding exon 3 of the SDHD gene, results from a C to T substitution at nucleotide position 242. The proline at codon 81 is replaced by leucine, an amino acid with similar properties. This alteration has been described in numerous cases of familial paraganglioma/pheochromocytoma (PGL-PCC), multifocal PGL-PCC, and sporadic PGL-PCC (Baysal BE et al. Science. 2000 Feb;287(5454):848-51; Baysal BE et al. J. Med. Genet. 2002 Mar;39(3):178-83; Astrom K et al. Hum. Genet. 2003 Aug;113(3):228-37; Milunsky JM et al. Am. J. Med. Genet. 2001 May;100(4):311-4) and has been shown to segregate with disease in PGL kindreds (Badenhop RF et al. Genes Chromosomes Cancer. 2001 Jul;31(3):255-63; Yeap PM et al. J. Clin. Endocrinol. Metab. 2011 Dec;96(12):E2009-13). A study consisting of 170 individuals with SDHD mutations, p.P81L carriers had a significantly lower risk for pheochromocytoma compared to other SDHD mutations (p=0.031) and presented almost exclusively with head/neck PGLs (Andrews KA et al. J. Med. Genet. 2018 Jun;55(6):384-394). One study reported that this alteration results in an increased succinate:fumarate ratio and decreased SDHD enzymatic activity; although the alteration produced a false-negative result using succinate:fumarate ratio in a different study using enzymatic levels as a method for screening for SDH mutations in a tumor with loss of heterozygosity and reduced SDH activity (Canu L et al. J. Clin. Endorcinol. Metab. 2014 Jul;99(7):2321-6; Richter S et al. J. Clin. Endocrinol. Metab. 2014 Oct;99(10):3903-11). It is believed that both founder effects and mutation recurrence contribute to the prevalence of this alteration in North America (Baysal BE et al. J. Med. Genet. 2002 Mar;39(3):178-83; Astrom K et al. Hum. Genet. 2003 Aug;113(3):228-37). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
UCLA Clinical Genomics Center, UCLA	RCV000007303	SCV000255463	pathogenic	Paragangliomas 1	2014-01-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000216073	SCV000279171	pathogenic	not provided	2018-12-05	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted SDHD c.242C>T at the cDNA level, p.Pro81Leu (P81L) at the protein level, and results in the change of a Proline to a Leucine (CCG>CTG). SDHD Pro81Leu is considered a recurrent pathogenic variant in the United States; it has been reported to segregate with disease in multiple kindreds with familial paraganglioma and was absent from healthy controls (Baysal 2000, Badenhop 2001, Milunsky 2001, Taschner 2001, Baysal 2002, Astrom 2003, Astuti 2003, Badenhop 2004, Mhatre 2004, Ricketts 2010, Xekouki 2015, Santi 2017). This variant has also been observed in individuals with a personal, but not family, history of paraganglioma (Taschner 2001, Baysal 2002, Astuti 2003, Badenhop 2004, Neumann 2004, Bacca 2013). Loss of heterozygosity has been noted in tumors of several individuals who carry SDHD Pro81Leu, with one tumor demonstrating significantly reduced SDH enzyme activity compared to wild-type (Baysal 2000, Richter 2014). RT-PCR of RNA isolated from paragangliomas of individuals harboring this variant showed monoallelic expression of the variant allele, indicating loss of expression of the wild-type allele in the tumor tissue (Badenhop 2001). SDHD Pro81Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the helical transmembrane domain (UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider SDHD Pro81Leu to be a pathogenic variant. Of note, variants in the SDHD gene exhibit a parent-of-origin effect and, if shown to be pathogenic, typically cause symptoms only if inherited from the father.
Invitae	RCV000627762	SCV000287817	pathogenic	Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3	2019-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces proline with leucine at codon 81 of the SDHD protein (p.Pro81Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (rs80338844, ExAC no frequency). This variant has been reported to segregate with head and neck paraganglioma (HNP) or pheochromocytoma in multiple families (PMID: 11391796, 15479192, 19454582, 21937622, 25494863), and has been reported as a recurrent variant found in numerous familial and sporadic cases of HNP (PMID: 10657297, 11897817, 21348866, 24436918, 23433498). ClinVar contains an entry for this variant (Variation ID: 6896). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV000999729	SCV000605086	pathogenic	not specified	2018-11-16	criteria provided, single submitter	clinical testing	The SDHD c.242C>T; p.Pro81Leu variant (rs80338844) is one of the most common variants reported in familial and sporadic cases of head and neck paraganglioma (PGL) (Andrews 2018, Astrom 2003, Baysal 2000, Baysal 2002, Sridhara 2013, Xekouki 2015). It has been reported to co-segregate with disease in several affected families (Astrom 2003, Baysal 2000, Xekouki 2015). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 6896), and it is observed on only six chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. The proline at codon 81 is well conserved across a variety of species and computational algorithms (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. References: Andrews KA et al. Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. J Med Genet. 2018 Jun;55(6):384-394. Astrom K et al. Altitude is a phenotypic modifier in hereditary paraganglioma type 1: evidence for an oxygen-sensing defect. Hum Genet. 2003 Aug;113(3):228-37. Baysal BE et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science. 2000 Feb 4;287(5454):848-51. Baysal BE et al. Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas. J Med Genet. 2002 Mar;39(3):178-83. Sridhara SK et al. Genetic testing in head and neck paraganglioma: who, what, and why? J Neurol Surg B Skull Base. 2013 Aug;74(4):236-40. Xekouki P et al. Pituitary adenoma with paraganglioma/pheochromocytoma (3PAs) and succinate dehydrogenase defects in humans and mice. J Clin Endocrinol Metab. 2015 May;100(5):E710-9.
Integrated Genetics/Laboratory Corporation of America	RCV000162448	SCV000698141	pathogenic	Hereditary cancer-predisposing syndrome	2017-08-21	criteria provided, single submitter	clinical testing	Variant summary: The SDHD c.242C>T (p.Pro81Leu) variant involves the alteration of a conserved nucleotide, resulting in a missense change that does not lie within a known functional domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 121894 control chromosomes tested in ExAC and published control cohorts. The variant has been reported in numerous patients, and has been found segregating with disease in families as well as in sporadic, non-familial cases. Based on the literature, the variant is considered a founder mutation and a well-known pathogenic allele. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000020519	SCV000711451	pathogenic	Hereditary Paraganglioma-Pheochromocytoma Syndromes	2016-09-21	criteria provided, single submitter	clinical testing	The p.Pro81Leu variant in SDHD has been reported in >25 individuals with paragan gliomas and/or pheochromocytomas (PGL/PCC), segregated with disease in at least 16 relatives from 7 families (Xekouki 2015, Sridhara 2013, Yeap 2011, Baysal 200 2, Mannelli 2006, Astrom 2003). This variant, along with loss of heterozygosity, has also been found as a somatic change in the tumor of an individual with an i solated pheochromocytoma (Gimm 2000). It has also been reported by other clinica l laboratories in ClinVar (Variation ID 6896). This variant has also been identi fied in 3/126674 of European chromosomes by the Genome Aggregation Database (gno mAD, http:/gnomad.broadinstitute.org; dbSNP rs80338844). This frequency is low e nough to be consistent with the frequency of hereditary PGL/PCC syndrome in the general population. In summary, this variant meets criteria to be classified as pathogenic for hereditary paraganglioma-pheochromocytoma syndrome in an autosoma l dominant manner based upon segregation studies and presence in multiple affect ed individuals. ACMG/AMP Criteria applied: PS4, PP1_Strong (Richards 2015).
Center for Human Genetics, Inc,Center for Human Genetics, Inc	RCV000007303	SCV000782285	pathogenic	Paragangliomas 1	2016-11-01	criteria provided, single submitter	clinical testing
Fulgent Genetics,Fulgent Genetics	RCV000763227	SCV000893859	pathogenic	Carney-Stratakis syndrome; Pheochromocytoma; Mitochondrial complex II deficiency; Paragangliomas 1	2018-10-31	criteria provided, single submitter	clinical testing
OMIM	RCV000007303	SCV000027499	pathogenic	Paragangliomas 1	2003-08-01	no assertion criteria provided	literature only
OMIM	RCV000007304	SCV000027500	pathogenic	Pheochromocytoma	2003-08-01	no assertion criteria provided	literature only
GeneReviews	RCV000020519	SCV000040976	pathologic	Hereditary Paraganglioma-Pheochromocytoma Syndromes	2012-08-30	no assertion criteria provided	curation	Converted during submission to Pathogenic.
OMIM	RCV000023206	SCV000044497	pathogenic	Paragangliomas 1 with sensorineural hearing loss	2003-08-01	no assertion criteria provided	literature only
Section on Medical Neuroendocrinolgy,National Institutes of Health	RCV000020519	SCV000599533	pathogenic	Hereditary Paraganglioma-Pheochromocytoma Syndromes		no assertion criteria provided	research
GenomeConnect, ClinGen	RCV000020519	SCV000607172	not provided	Hereditary Paraganglioma-Pheochromocytoma Syndromes		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.