Submissions for variant NM_003002.4(SDHD):c.148C>G (p.His50Asp)

dbSNP: rs779249550

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497964	SCV000589392	likely pathogenic	not provided	2017-05-19	criteria provided, single submitter	clinical testing	The H50D variant has previously been reported in at least one individual with bilateral carotid body paragangliomas (Kung and Oh, 2011). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The H50D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on currently available evidence, H50D is a strong candidate for a pathogenic variant. However, the possibility it could be a rare benign variant cannot be excluded.
Ambry Genetics	RCV000569506	SCV000664535	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-07-26	criteria provided, single submitter	clinical testing	The p.H50D variant (also known as c.148C>G), located in coding exon 2 of the SDHD gene, results from a C to G substitution at nucleotide position 148. The histidine at codon 50 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with SDHD-related disease (Ambry internal data). This alteration was reported in a woman with bilateral carotid body paragangliomas (PGLs); her brother and a paternal uncle's daughter were also affected with PGLs. Familial testing determined that the patient's affected brother was positive for this alteration and their unaffected mother was negative, consistent with paternal inheritance (Kung JT, Oh DK. Identification of an Occult Functioning Cardiac Paraganglioma in a Patient with a Novel SDHD Mutation Causing Familial Paraganglioma Syndrome [abstract]. In: The Endocrine Society's 93rd Annual Meeting & Expo. 2011 Jun 4-7; Boston. Abstract P2-664). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV002230973	SCV000762665	likely pathogenic	Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas with sensorineural hearing loss; Cowden syndrome 3	2022-12-06	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 431847). This missense change has been observed in individuals with paraganglioma (PMID: 34906457; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 50 of the SDHD protein (p.His50Asp). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Section on Medical Neuroendocrinolgy, National Institutes of Health	RCV000505346	SCV000599536	uncertain significance	Hereditary pheochromocytoma-paraganglioma		no assertion criteria provided	research