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

gnomAD frequency: 0.00001  dbSNP: rs80338844

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162448	SCV000212801	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-15	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; Shulskaya MV et al. Int J Neurosci, 2018 Dec;128:1174-1179; Enríquez-Vega ME et al. Cir Cir, 2019;86:33-37; McCrary HC et al. JAMA Otolaryngol Head Neck Surg, 2019 07;145:641-646; Richter S et al. Genet Med, 2019 03;21:705-717; (Greenberg SE et al. Genet Med, 2020 12;22:2101-2107; Smith JD et al. OTO Open Mar;5:2473974X21995453) 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	2021-12-06	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23175444, 15328326, 28748451, 25494863, 19454582, 24758185, 30375904, 29386252, 11156372, 26259135, 25014000, 11897817, 11343322, 11391798, 12811540, 19802898, 26916530, 11391796, 26113606, 25326637, 25695889, 22290790, 15235042, 14974914, 17102085, 15479192, 10657297, 28179334, 29341163, 24102379, 23433498, 21348866, 24436918, 29681642, 30658386, 29777207, 30050099, 30877234, 22575350, 29625052, 31492822, 32741965, 30787465, 33087929)
Invitae	RCV002228002	SCV000287817	pathogenic	Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas with sensorineural hearing loss; Cowden syndrome 3	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 81 of the SDHD protein (p.Pro81Leu). This variant is present in population databases (rs80338844, gnomAD 0.006%). This missense change has been observed in individual(s) with head and neck paraganglioma (HNP) or pheochromocytoma (PMID: 10657297, 11391796, 11897817, 15479192, 19454582, 21348866, 21937622, 23433498, 24436918, 25494863). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6896). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SDHD protein function. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000216073	SCV000605086	pathogenic	not provided	2021-11-01	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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, Mass General Brigham Personalized Medicine	RCV000020519	SCV000711451	pathogenic	Hereditary pheochromocytoma-paraganglioma	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, nuclear type 1; Paragangliomas 1	2018-10-31	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV002221470	SCV002499223	likely pathogenic	Mitochondrial complex II deficiency, nuclear type 1	2022-01-25	criteria provided, single submitter	clinical testing	PS4, PM2, PP3
Revvity Omics, Revvity	RCV000216073	SCV003825501	pathogenic	not provided	2022-09-27	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000007304	SCV003925264	pathogenic	Pheochromocytoma	2022-09-12	criteria provided, single submitter	clinical testing	The c.242C>T p.(Pro81Leu) variant identified in the SDHD gene is a known Pathogenic variant that has been reported in multiple familial and sporadic cases of head and neck paraganglioma or pheochromocytoma [PMID: 10657297, 29625052, 15479192, 30375904, 11391796, 11897817,30877234], and has been deposited in ClinVar as Pathogenic/Likely Pathogenic by multiple independent laboratories [ClinVar ID: 6896]. In one study, of 53 individuals with detailed clinical information and carrying the p.(Pro81Leu) variant, 15 were asymptomatic, 37 had head and neck paraganglioma (HNPGL) (two metastatic) and 1 had phaeochromocytoma and paraganglioma (PPGL). Authors concluded that the p.(Pro81Leu) variant carriers manifest almost exclusively with HNPGL, while other SDHD pathogenic variants predispose to both HNPGL and PPGL [PMID: 29386252]. The c.242C>T variant is observed in 8 out of 590,232 heterozygous alleles (no homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8) suggesting it is not a common benign variant in the populations represented in those databases. The variant is located in exon 3 of this 4-exon gene, and is predicted to replace an evolutionarily conserved Proline amino acid with Leucine at position 81 of the encoded protein. In silico predictions are in favor of damaging effect for p.(Pro81Leu) [REVEL score = 0.91]. Based on available evidence, the c.242C>T p.(Pro81Leu) variant identified in the SDHD gene is reported as Pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000007303	SCV004175324	pathogenic	Paragangliomas 1	2022-11-09	criteria provided, single submitter	clinical testing	The SDHD c.242C>T variant is classified as Pathogenic (PM2, PP3, PP1_Strong) The SDHD c.242C>T variant is a single nucleotide change in exon 3/4 of the SDHD gene, which is predicted to change the amino acid proline at position 81 in the protein to leucine. The variant has been reported in many patients with paraganglioma and has been suggested to be a founder variant (PMID:10657297, 11391796, 11897812, 19454582,21348866, 23433498, 25494863) (PS4). The variant is rare in population databases (gnomAD allele frequency = 0.0013%; 2 het and 0 hom in 152182 sequenced alleles; highest frequency = 0.0029%, Non-Finnish European population) (PM2). This variant co-segregates with disease (PMID:21937622, 10657297, 29386252) (PP1_strong). Computational predictions strongly support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs80338844) and as disease causing in the HGMD database (CM000207). It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 6896).
Baylor Genetics	RCV003472995	SCV004203091	pathogenic	Mitochondrial complex 2 deficiency, nuclear type 3	2023-10-10	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000216073	SCV004220344	pathogenic	not provided	2022-05-06	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000021 (6/282810 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals/families with paraganglioma and/or pheochromocytoma (PMIDs: 30877234 (2019), 30375904 (2018), 29625052 (2018), 25494863 (2015), 24436918 (2013), 23433498 (2013), 21348866 (2012), 21348866 (2011), 19454582 (2009), 15479192 (2004), 11897817 (2002), 11391796 (2001), 10657297 (2000)), and is found to co-segregate with disease in multiple families (PMIDs: 11391796 (2001) and 21937622 (2011)). An experimental study using a humanized yeast construct has reported this variant results in oxidative growth, SDH activity, oxygen consumption and mtDNA mutability similar to WT (PMID: 23175444 (2013), however, studies using tumor tissue have demonstrated that this variant results in reduced enzyme activity (PMID: 24758185) and increased fumarate:succinate ratio (PMID: 24758185 (2014) and 30050099 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000216073	SCV004224505	pathogenic	not provided	2023-05-10	criteria provided, single submitter	clinical testing	PP1_strong, PP3, PP4, PM2, PS4_moderate
Color Diagnostics, LLC DBA Color Health	RCV000007303	SCV004362302	pathogenic	Paragangliomas 1	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 81 of the SDHD protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that succinate dehydrogenase complexes with this SDHD variant exhibit lower SDH enzyme activity observed via a higher succinate to fumarate metabolite ratio (PMID: 24758185, 25014000, 30050099). This variant has been reported in numerous individuals affected with pheochromocytoma/paraganglioma (PMID: 8981955, 10657297, 11343322, 11391796, 11391798, 11897817, 12811540, 14974914, 15235042, 15328326, 15479192, 17102085, 19454582, 21937622, 21348866, 22290790, 22575350, 23433498, 23666964, 24436918, 24102379, 25326637, 25494863, 25695889, 29386252, 29625052, 29681642, 29777207, 30050099, 30375904, 31492822). It has been also shown that this variant segregates with disease (PMID: 8981955, 11391796, 11897817, 15479192, 22575350, 25695889). This variant has been identified in 6/282810 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
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	not provided	Hereditary pheochromocytoma-paraganglioma		no assertion provided	literature only
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 pheochromocytoma-paraganglioma		no assertion criteria provided	research
GenomeConnect, ClinGen	RCV000020519	SCV000607172	not provided	Hereditary pheochromocytoma-paraganglioma		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.