Submissions for variant NM_006642.5(SDCCAG8):c.740+356C>T

gnomAD frequency: 0.00006  dbSNP: rs397515337

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000000077	SCV000693908	pathogenic	Bardet-Biedl syndrome 16	2017-06-26	criteria provided, single submitter	research	PVS1: This is an intronic variant in most transcripts but there is functional evidence in the literature that it results in altered splicing and significantly reduced protein levels (PMID: 20835237). It is annotated as a missense here but that only applies to 1 transcript. PP1 it cosegregates in 1 large Gypsy family with 5 affected individuals in 2 sibships (PMID: 22190896). PM2 rare in population databases (AC = 2 in gnomAD).
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000760978	SCV000890883	pathogenic	Senior-Loken syndrome 7	2018-06-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265541	SCV002548420	pathogenic	Bardet-Biedl syndrome	2022-05-17	criteria provided, single submitter	clinical testing	Variant summary: SDCCAG8 c.740+356C>T is located at a position not widely known to affect splicing. 4/4 computational tools predict no significant impact on normal splicing. However, at least one publication reports experimental evidence that this variant affects mRNA splicing. The variant allele was found at a frequency of 0.00012 in 8058 control chromosomes. c.740+356C>T has been reported in the literature in multiple individuals affected with retinal-renal ciliopathy. These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002476900	SCV002783103	likely pathogenic	Senior-Loken syndrome 7; Bardet-Biedl syndrome 16	2021-09-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003415592	SCV004108322	likely pathogenic	SDCCAG8-related condition	2022-12-27	criteria provided, single submitter	clinical testing	The SDCCAG8 c.740+356C>T variant is predicted to interfere with splicing. This variant has been reported in the homozygous state in 5 affected individuals from two related Roma families with Bardet-Biedl syndrome (BBS) (Otto et al. 2010. PubMed ID: 20835237; Schaefer et al. 2011. PubMed ID: 22190896). Although this family was diagnosed with BBS, they were initially recruited due to acute manifestation of chronic renal failure coupled with respiratory defects. This deep intronic variant was predicted to disrupt an exonic splicing enhancer which was confirmed by cDNA sequencing (Otto et al. 2010. PubMed ID: 20835237). This variant was also described in the compound heterozygous state in an individual with Senior-Loken syndrome (Tay and Vincent. 2020. PubMed ID: 32432520) and in the homozygous state in an individual with suspected retinal disease (Weisschuh et al. 2020. PubMed ID: 32531858, supplementary data). Lastly, this variant was detected, along with a second causative variant, in another individual with Bardet-Biedl syndrome (Meyer et al. 2022. PubMed ID: 35112343). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-243468435-C-T). This variant is interpreted as likely pathogenic.
OMIM	RCV000000077	SCV000020220	pathogenic	Bardet-Biedl syndrome 16	2011-09-01	no assertion criteria provided	literature only