Submissions for variant NM_024685.4(BBS10):c.765G>A (p.Met255Ile)

gnomAD frequency: 0.00072  dbSNP: rs139658279

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224072	SCV000281441	likely benign	not provided	2016-01-18	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Eurofins Ntd Llc (ga)	RCV000224072	SCV000331887	uncertain significance	not provided	2015-09-19	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000625184	SCV000744060	likely benign	Bardet-Biedl syndrome 1	2016-05-04	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000625184	SCV000745511	likely benign	Bardet-Biedl syndrome 1	2017-05-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000667212	SCV000791630	uncertain significance	Bardet-Biedl syndrome 10	2017-05-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000801717	SCV000941509	uncertain significance	Bardet-Biedl syndrome	2022-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 255 of the BBS10 protein (p.Met255Ile). This variant is present in population databases (rs139658279, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 20120035). ClinVar contains an entry for this variant (Variation ID: 235677). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BBS10 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.
Illumina Laboratory Services, Illumina	RCV000667212	SCV001266852	uncertain significance	Bardet-Biedl syndrome 10	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV000224072	SCV002526232	uncertain significance	not provided	2022-06-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Identified in individuals with Bardet-Biedl syndrome in published literature who were found to have an alternate molecular basis for their phenotype (Manara et al., 2019; Hjortshoj et al., 2010); This variant is associated with the following publications: (PMID: 20120035, 31196119)
Mayo Clinic Laboratories, Mayo Clinic	RCV000224072	SCV005408366	uncertain significance	not provided	2024-05-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001706242	SCV005884419	uncertain significance	not specified	2024-12-26	criteria provided, single submitter	clinical testing	Variant summary: BBS10 c.765G>A (p.Met255Ile) 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 0.0006 in 249212 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in BBS10 causing Bardet-Biedl Syndrome (0.0006 vs 0.0012), allowing no conclusion about variant significance. c.765G>A has been reported in the literature in heterozygous individuals affected with Bardet-Biedl Syndrome or Retinitis Pigmentosa who also had biallelic variants in other genes (Hjortshoj_2010, Manara_2019, Jespersgaard_2019). These reports do not provide unequivocal conclusions about association of the variant with Bardet-Biedl Syndrome. Some of the co-occurring variants are known to be pathogenic (BBS2 c.661del, p.Leu221fs; BBS1 c.1285dup, p.Arg429fs; PROM1 c.2461C>T, p.Arg821Ter), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20120035, 31196119, 30718709). ClinVar contains an entry for this variant (Variation ID: 235677). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000667212	SCV001453631	uncertain significance	Bardet-Biedl syndrome 10	2019-12-18	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001706242	SCV001919852	benign	not specified		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003417800	SCV004109110	likely benign	BBS10-related disorder	2024-09-17	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).