ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.148C>G (p.His50Asp) (rs779249550)

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Total submissions: 4
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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 2019-12-13 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 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 RCV000641047 SCV000762665 likely pathogenic Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3 2020-09-17 criteria provided, single submitter clinical testing This sequence change replaces histidine with aspartic acid at codon 50 of the SDHD protein (p.His50Asp). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with paraganglioma (Invitae). ClinVar contains an entry for this variant (Variation ID: 431847). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). 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 Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

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