Submissions for variant NM_001011.4(RPS7):c.-19+1G>C

dbSNP: rs1064796859

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484441	SCV000573990	uncertain significance	not provided	2017-03-13	criteria provided, single submitter	clinical testing	The c.-19+1 G>C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. Several in-silico splice prediction models predict that c.-19+1 G>C destroys the canonical splice donor site of exon 1; however, exon 1 is non-coding. In the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004594065	SCV005087138	likely pathogenic	Diamond-Blackfan anemia 8	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Diamond-Blackfan anaemia 8 (MIM#612563). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). However, this variant is located within the 5'-UTR and is predicted to result in the loss of the transcription start site. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tool and affected nucleotide is highly conserved. (SP) 0702 - Other variants comparable to the one identified in this case have strong previous evidence for pathogenicity. A substitution affecting the same nucleotide, c.-19+1G>A, was regarded as pathogenic in ClinVar. Another change, c.-19+1G>T, segregated in a Russian family with Diamond-Blackfan anaemia (DBA) and was shown to dramatically decrease mRNA and protein levels (PMID: 36057918). In addition, c.-19+2T>C was detected de novo in an individual with DBA (PMID: 25946618). (SP) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been regarded as VUS by GeneDx in an individual with DBA (ClinVar, personal communication) as well as in a Dutch DBA patient (PMID: 29114930). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1206 - This variant has been shown to be paternally inherited but is suspected mosaic in the father. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign