Submissions for variant NM_003001.5(SDHC):c.179+1G>C

dbSNP: rs1057517818

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414585	SCV000490792	likely pathogenic	not provided	2016-04-06	criteria provided, single submitter	clinical testing	The c.179+1G>C splice site variant in the SDHC gene has not bee reported previously as a pathogenicvariant, nor as a benign variant, to our knowledge. This variant was not observed in approximately6,500 individuals of European and African American ancestry in the NHLBI Exome SequencingProject, indicating it is not a common benign variant in these populations. The c.179+1G>C variantdestroys the canonical splice donor site in intron 3, and is expected to cause abnormal gene splicing.Based on the available information, c.179+1G>C is a strong candidate for a pathogenic variant;however, the possibility it may be a rare benign variant cannot be excluded.
Ambry Genetics	RCV000492312	SCV000581223	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-06-04	criteria provided, single submitter	clinical testing	The c.179+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 3 of the SDHC gene. This variant has been observed in at least one individual with a personal and/or family history that is consistent with SDHC-associated disease (Ambry internal data).This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001047084	SCV001211019	likely pathogenic	Gastrointestinal stromal tumor; Paragangliomas 3	2020-02-04	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 3 of the SDHC gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SDHC-related conditions. ClinVar contains an entry for this variant (Variation ID: 372501). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SDHC are known to be pathogenic (PMID: 19454582, 24758179). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323526	SCV004029461	likely pathogenic	Hereditary pheochromocytoma-paraganglioma	2023-07-10	criteria provided, single submitter	clinical testing	Variant summary: SDHC c.179+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251440 control chromosomes (gnomAD). To our knowledge, no occurrence of c.179+1G>C in individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc.	RCV004591140	SCV005083667	likely pathogenic	Paragangliomas 3	2024-05-29	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.