Submissions for variant NM_003002.4(SDHD):c.34G>A (p.Gly12Ser)

gnomAD frequency: 0.00706  dbSNP: rs34677591

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000122006	SCV000206155	benign	not specified	2014-04-23	criteria provided, single submitter	clinical testing	Gly12Ser in exon 1 of SDHD: This variant has been identified in 1% (36/3612) of patient chromosomes with varying cancer types that included pheochromocytoma, p araganglioma, Cowden and Cowden-like syndromes, and athersclerosis (Gimm 2000, L eube 2004, Ni 2008, Ni 2012, Johnston 2012, Lendavi 2012, Rattenbery 2013). Howe ver, this variant has also been identified in 1.1% (96/8594) European American c hromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu) and 2.5% (6/330) of Puerto Rican and Colombian chromosomes from the 1000 Genomes Project (dbSNP rs34677591). Furthermore, glycine (Gly) at position 12 is not c onserved in mammals or evolutionarily distant species and 5 mammals (tree shrew, vole, hamster, mouse, and rat) carry a serine (Ser) at this position, supportin g that this change may be tolerated. Two studies have shown that this variant ma y modify cancer risk in individuals with pathogenic variants in familial cancer syndrome genes (Ni 2012, Lindavi 2012), though these findings have not been repl icated. In summary, due to the high and equal allele frequency in patient and co ntrol chromosomes and the lack of conservation, this variant is unlikely to cont ribute to Mendelian disease.
Ambry Genetics	RCV000162470	SCV000212833	benign	Hereditary cancer-predisposing syndrome	2015-05-22	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV002228001	SCV000261731	benign	Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas with sensorineural hearing loss; Cowden syndrome 3	2024-02-01	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000007300	SCV000297096	benign	Paragangliomas 1	2015-11-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000122006	SCV000309340	benign	not specified		criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000122006	SCV000332509	benign	not specified	2015-07-07	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000007302	SCV000367342	likely benign	Pheochromocytoma	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000122006	SCV000514600	benign	not specified	2017-11-03	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000122006	SCV000602187	benign	not specified	2021-06-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034697	SCV000605088	benign	not provided	2023-10-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000034697	SCV000698143	benign	not provided	2016-05-25	criteria provided, single submitter	clinical testing	Variant summary: The SDHD c.34G>A (p.Gly12Ser) variant involves the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPs&GO and MutationTaster not captured due to low reliability index). Functional studies of G12S in the literature have shown mixed results. G12S has been shown to increase ROS levels and activated signaling down the AKT and MAPK pathways, as well as inducing migration and increasing resistance to apoptosis. However, the results of these functional studies may not be a reflection of the in vivo consequence in relation to the PGL/PCC or Cowden Syndrome phenotypes.Population level data suggest that this variant lies in the benign spectrum. Although this variant has been identified in CS, CS-like, and cancer patients, it was also found in 881/121216 control chromosomes (5 homozygotes) at a frequency of 0.007268, which is approximately 4652 times the estimated maximal expected allele frequency of a pathogenic SDHD variant (0.0000016), suggesting this variant is likely a benign polymorphism. Additionally, it was found at an allele frequency of >1% in both the European non-Finnish and other subpopulations of ExAC. Sequence alignment indicates the occurrences in ExAC are unlikely to be from the pseudogenes.Furthermore, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign.
Mendelics	RCV000988742	SCV001138592	likely benign	Carney-Stratakis syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000122006	SCV001422584	uncertain significance	not specified	2020-01-22	criteria provided, single submitter	curation	The p.Gly12Ser variant in SDHD has been reported in at least 18 individuals with Cowden or Cowden-like Syndrome (PMID: 21979946, 18678321), 8 individuals with pheochromocytoma or paraganglioma (PMID: 11156372, 11526495, 12111639, 12386824, 15032977, 23666964), in tumors from 2 individuals (PMID: 12007193), in other cohorts with other phenotypes (PMID: 24728327, 22703879), and has been identified in 1.019% (1316/129110) of European (non-Finnish) chromosomes, including 8 homozygotes, 1.013% (105/10370) of Ashkenazi Jewish chromosomes, including 1 homozygote, and 0.9173% (325/5430) of Latino chromosomes, including 3 homozygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs34677591). This variant has also been reported in ClinVar as a VUS, likely benign, and benign variant (Variation ID: 6895). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population and pathogenic variants in this gene have incomplete penetrance (PMID: 29386252). In vitro functional studies provide some evidence that the p.Gly12Ser variant may impact growth pathways and apoptosis (PMID: 18678321, 21979946, 25149476). However, these types of assays may not accurately represent biological function and a yeast model did not match a cancer-related phenotype (PMID: 23175444). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The Glycine (Gly) at position 12 is not highly conserved in mammals and evolutionary distant species, and 5 species (Chinese tree shrew, prairie vole, chinese hamster, mouse, rat) carry a Serine (Ser), supporting that this change at this position may be tolerated. One additional variant, resulting in a different amino acid change at the same position, p.Gly12Asp, has been reported as a VUS in association with disease in ClinVar (Variation ID: 465235). In summary, the clinical significance of the p.Gly12Ser variant is uncertain. ACMG/AMP Criteria applied: BS1, PS4, PS3_Moderate (Richards 2015).
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000034697	SCV002010034	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001807000	SCV002054697	benign	Mitochondrial complex 2 deficiency, nuclear type 3	2021-07-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000007300	SCV002054698	benign	Paragangliomas 1	2021-07-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000007302	SCV002054699	benign	Pheochromocytoma	2021-07-15	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000122006	SCV002071034	benign	not specified	2021-11-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034697	SCV002497177	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	SDHD: BP4, BS1, BS2
Sema4, Sema4	RCV000162470	SCV002535339	benign	Hereditary cancer-predisposing syndrome	2020-08-21	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000122006	SCV002549992	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000007300	SCV004362298	benign	Paragangliomas 1	2022-06-09	criteria provided, single submitter	clinical testing
OMIM	RCV000007299	SCV000027495	uncertain significance	Cowden syndrome 3	2008-08-01	no assertion criteria provided	literature only
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034697	SCV000043497	no known pathogenicity	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Benign.
ITMI	RCV000122006	SCV000086217	not provided	not specified	2013-09-19	no assertion provided	reference population
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000034697	SCV001800256	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000122006	SCV001807158	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000122006	SCV001955473	benign	not specified		no assertion criteria provided	clinical testing