Submissions for variant NM_003002.4(SDHD):c.101T>G (p.Phe34Cys)

gnomAD frequency: 0.00016  dbSNP: rs141802836

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002228410	SCV000287810	uncertain significance	Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas with sensorineural hearing loss; Cowden syndrome 3	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 34 of the SDHD protein (p.Phe34Cys). This variant is present in population databases (rs141802836, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with SDHD-related conditions. ClinVar contains an entry for this variant (Variation ID: 135196). 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) performed at Invitae indicates that this missense variant is not expected to disrupt SDHD protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000569765	SCV000675108	likely benign	Hereditary cancer-predisposing syndrome	2024-02-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
GeneDx	RCV001545828	SCV001765234	uncertain significance	not provided	2023-11-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in at least one individual with a personal history of pheochromocytoma and/or paraganglioma (PMID: 34906457); This variant is associated with the following publications: (PMID: 24728327, 34906457)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003230259	SCV003928129	uncertain significance	Paragangliomas 1	2023-04-24	criteria provided, single submitter	clinical testing	The SDHD c.101T>G (p.Phe34Cys) missense change has a maximum subpopulation frequency of 0.036% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with SDHD-associated conditions. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003997358	SCV004845023	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with cysteine at codon 34 of the SDHD protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SDHD-related disorders in the literature. This variant has been identified in 11/282870 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
ITMI	RCV000122008	SCV000086219	not provided	not specified	2013-09-19	no assertion provided	reference population
PreventionGenetics, part of Exact Sciences	RCV004748588	SCV005351215	uncertain significance	SDHD-related disorder	2024-07-16	no assertion criteria provided	clinical testing	The SDHD c.101T>G variant is predicted to result in the amino acid substitution p.Phe34Cys. This variant was reported in an individual with pheochromocytoma and/or paraganglioma, however its pathogenicity was not supported by functional or familial segregation studies (Garrett et al. 2022. PubMed ID: 34906457). This variant is reported in 0.036% of alleles in individuals of African descent in gnomAD. It is reported in ClinVar with conflicting interpretations of likely benign and uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/135196/evidence/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.