Submissions for variant NM_198428.3(BBS9):c.2258A>T (p.Glu753Val)

gnomAD frequency: 0.00066  dbSNP: rs61764068

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000417647	SCV000523957	uncertain significance	not provided	2022-10-12	criteria provided, single submitter	clinical testing	Observed multiple times with a second variant in unrelated patients in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in all cases (Lee et al., 2015; Comander et al., 2017; Kleinendorst et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29970488, 25910913, 28981474, 31888296)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083313	SCV001002494	likely benign	Bardet-Biedl syndrome	2024-12-27	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001165275	SCV001327455	uncertain significance	Bardet-Biedl syndrome 9	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Ambry Genetics	RCV002521642	SCV003526817	likely benign	Inborn genetic diseases	2022-01-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004816660	SCV005071662	uncertain significance	Retinal dystrophy	2023-01-01	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000417647	SCV001551747	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BBS9 p.Glu708Val variant was not identified in the literature but was identified in dbSNP (ID: rs61764068), ClinVar (classified as a VUS by GeneDx), Cosmic (FATHMM prediction of pathogenic; score=0.99), and LOVD 3.0. The variant was identified in control databases in 211 of 282262 chromosomes at a frequency of 0.000748 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 41 of 10348 chromosomes (freq: 0.003962), South Asian in 33 of 30614 chromosomes (freq: 0.001078), European (non-Finnish) in 118 of 128672 chromosomes (freq: 0.000917), African in 7 of 24972 chromosomes (freq: 0.00028), Latino in 9 of 35394 chromosomes (freq: 0.000254), Other in 1 of 7202 chromosomes (freq: 0.000139) and European (Finnish) in 2 of 25114 chromosomes (freq: 0.00008); it was not observed in the East Asian population. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, NNSPLICE, and GeneSplicer) do not predict a difference in splicing. The p.Glu708 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, BLOSUM, and MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003912685	SCV004732074	likely benign	BBS9-related disorder	2022-06-30	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).