ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.305A>T (p.His102Leu)

dbSNP: rs104894302
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000566289 SCV000664577 pathogenic Hereditary cancer-predisposing syndrome 2021-06-23 criteria provided, single submitter clinical testing The p.H102L variant (also known as c.305A>T), located in coding exon 3 of the SDHD gene, results from an A to T substitution at nucleotide position 305. The histidine at codon 102 is replaced by leucine, an amino acid with similar properties. This mutation has been reported in multiple individuals with paraganglioma-pheochromocytoma (PGL/PCC) syndrome (Baysal BE et al. Science, 2000 Feb;287:848-51; Astrom K et al. Hum Genet, 2003 Aug;113:228-37; Ambry internal data). Other alterations at the same codon, p.H102N and p.H102Y, have been detected in patients with PGL/PCC syndrome (Piccini V et al. Endocr. Relat. Cancer. 2012 Apr;19(2):149-55; Bacca A et al. Head Neck. 2013 Jan;35(1):23-7; Benn DE et al. Endocr. Relat. Cancer. 2015 Aug;22:T91-103). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp RCV002228003 SCV000762668 pathogenic Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas with sensorineural hearing loss; Cowden syndrome 3 2021-07-01 criteria provided, single submitter clinical testing This sequence change replaces histidine with leucine at codon 102 of the SDHD protein (p.His102Leu). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with paragangliomas (Invitae). It has also been observed to segregate with disease in related individuals (PMID: 10657297, 12811540). ClinVar contains an entry for this variant (Variation ID: 6898). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.His102 amino acid residue in SDHD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22241717, Invitae, external communication). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000007307 SCV000027504 pathogenic Paragangliomas 1 2000-02-04 no assertion criteria provided literature only

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