ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.94_95del (p.Ala33fs) (rs397514034)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486940 SCV000568555 pathogenic not provided 2017-05-31 criteria provided, single submitter clinical testing This deletion of two nucleotides in SDHD is denoted c.94_95delTC at the cDNA level and p.Ala33IlefsX35 (A33IfsX35) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TATC[delTC]AGCA. The deletion causes a frameshift which changes an Alanine to an Isoleucine at codon 33, and creates a premature stop codon at position 35 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. SDHD c.94_95delTC, also reported as SDHD F933>X67, has been identified in several individuals with pheochromocytoma and/or paraganglioma, and was found to segregate with disease in at least two families (Astuti 2001, Marvin 2009, van Nederveen 2009, Buffet 2012, Kim 2014). Based on currently available information, we consider this variant to be pathogenic.
Ambry Genetics RCV000492163 SCV000581234 pathogenic Hereditary cancer-predisposing syndrome 2017-04-12 criteria provided, single submitter clinical testing The c.94_95delTC pathogenic mutation, located in coding exon 2 of the SDHD gene, results from a deletion of two nucleotides at nucleotide positions 94 to 95, causing a translational frameshift with a predicted alternate stop codon (p.A33Ifs*35). This pathogenic mutation, referred to as F933>X67, has been reported in a 15 year old patient with a personal and family history of head and neck paragangliomas (Marvin et al. Head and Neck. 2009.31(5): 689-694). This pathogenic mutation was also reported in a family diagnosed with multiple pheochromocytomas (Astuti et al. Lancet. 2001. 357(9263):1181-1182). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000820475 SCV000961190 pathogenic Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3 2019-12-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ala33Ilefs*35) in the SDHD gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in families affected with pheochromocytoma and/or paraganglioma, and has been described to segregate with disease (PMID: 11323050, 19072999). This variant is also known as F933>X67 in the literature. ClinVar contains an entry for this variant (Variation ID: 6908). Loss-of-function variants in SDHD are known to be pathogenic (PMID: 19454582, 19802898). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000007317 SCV000027514 pathogenic Paragangliomas 1 2001-04-14 no assertion criteria provided literature only

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