ClinVar Miner

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

dbSNP: rs1057517818
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Total submissions: 4
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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 2016-07-29 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 was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.005% (greater than 20000 alleles tested) in our clinical cohort. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Invitae RCV001047084 SCV001211019 likely pathogenic Gastrointestinal stromal tumor; Paragangliomas 3 2020-02-04 criteria provided, single submitter clinical testing 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. 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). 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). This variant is not present in population databases (ExAC no frequency). 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.
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.

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