ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.34G>A (p.Gly12Ser) (rs34677591)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 ( 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 General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Invitae RCV001083654 SCV000261731 benign Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3 2020-12-01 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,PreventionGenetics RCV000122006 SCV000309340 benign not specified criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000122006 SCV000332509 benign not specified 2015-07-07 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 2017-06-13 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283667 SCV000605088 benign none provided 2020-04-30 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
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
Broad Institute Rare Disease Group, Broad Institute RCV000122006 SCV001422584 uncertain significance not specified 2020-01-22 no assertion criteria provided 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,; 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).
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
Human Genetics - Radboudumc,Radboudumc RCV000122006 SCV001955473 benign not specified no assertion criteria provided clinical testing

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