Submissions for variant NM_024685.4(BBS10):c.1189A>G (p.Ile397Val)

gnomAD frequency: 0.00005  dbSNP: rs202042386

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002308629	SCV002600590	likely pathogenic	Bardet-Biedl syndrome	2022-10-19	criteria provided, single submitter	clinical testing	Variant summary: BBS10 c.1189A>G (p.Ile397Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 282676 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BBS10 causing Bardet-Biedl Syndrome (6e-05 vs 0.0012), allowing no conclusion about variant significance. c.1189A>G has been reported in the literature in three homozygous individuals affected with Obesity and Diabetes, Type 2 (Lim_2014), which are phenotypes associated with Bardet-Biedl Syndrome (MIM #615987). These data indicate that the variant is likely to be associated with disease. When assayed for rescue functionality in a Zebrafish Morphilino system, the variant could not rescue the convergent extension defect observed in bbs10 knockdown animals, indicating loss-of-function (Lim_2014). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002308629	SCV003023082	uncertain significance	Bardet-Biedl syndrome	2022-05-08	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 397 of the BBS10 protein (p.Ile397Val). This variant is present in population databases (rs202042386, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with BBS10-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV004719254	SCV005325124	uncertain significance	not provided	2023-07-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25439097)
Fulgent Genetics, Fulgent Genetics	RCV005002824	SCV005629240	likely pathogenic	Bardet-Biedl syndrome 10	2024-05-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003418448	SCV004109465	uncertain significance	BBS10-related disorder	2024-03-08	no assertion criteria provided	clinical testing	The BBS10 c.1189A>G variant is predicted to result in the amino acid substitution p.Ile397Val. This variant has been reported in the homozygous state in three individuals with type 2 diabetes and high BMI; however none of the individuals had cardinal features of Bardet-Biedl syndrome (Lim et al 2014. PubMed ID: 25439097). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.