Submissions for variant NM_000136.3(FANCC):c.1533+1G>C

gnomAD frequency: 0.00001  dbSNP: rs753885687

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409707	SCV000486410	likely pathogenic	Fanconi anemia complementation group C	2016-05-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001380007	SCV001577930	pathogenic	Fanconi anemia	2023-08-05	criteria provided, single submitter	clinical testing	This variant disrupts a region of the FANCC protein in which other variant(s) (p.Arg548*) have been determined to be pathogenic (PMID: 8103176, 8882868, 24584348). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 370968). This variant has not been reported in the literature in individuals affected with FANCC-related conditions. This variant is present in population databases (rs753885687, gnomAD 0.006%). This sequence change affects a donor splice site in intron 14 of the FANCC gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product.
Revvity Omics, Revvity	RCV000409707	SCV002024579	likely pathogenic	Fanconi anemia complementation group C	2021-08-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002392933	SCV002703879	uncertain significance	Hereditary cancer-predisposing syndrome	2020-09-23	criteria provided, single submitter	clinical testing	The c.1533+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 13 of the FANCC gene. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. 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. The exact functional effect of the missing amino acids is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000409707	SCV002768136	likely pathogenic	Fanconi anemia complementation group C	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely pathogenic. The following criteria are met: 0102 - Loss of function is a mechanism of disease in this gene and is associated with Fanconi anaemia of complementation group C (MIM#227645). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (2 heterozygotes, 0 homozygotes). (SP) 0311 - Two alternative nucleotide changes at the same canonical splice site are present in gnomAD (v3) (highest allele: 1 heterozygote, 0 homozygotes). (I) 0508 - In silico predictions for abnormal splicing are conflicting. (I) 0803 - This variant has limited previous evidence of pathogenicity and has previously been reported as likely pathogenic and pathogenic in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 0703 - Other canonical splice site variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. c.1533+1G>T and c.1533+2T>C have been reported as pathogenic in ClinVar. (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Neuberg Centre For Genomic Medicine, NCGM	RCV000409707	SCV004100588	pathogenic	Fanconi anemia complementation group C		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000409707	SCV004196672	likely pathogenic	Fanconi anemia complementation group C	2024-02-21	criteria provided, single submitter	clinical testing