ClinVar Miner

Submissions for variant NM_024685.4(BBS10):c.1736A>G (p.Lys579Arg) (rs141521925)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000246690 SCV000052050 uncertain significance not specified 2018-02-28 criteria provided, single submitter clinical testing Variant summary: BBS10 c.1736A>G (p.Lys579Arg) results in a conservative amino acid change located in the Intermediate domain (Stoetzel_NatGen_2006) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00052 in 120630 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BBS10 causing Bardet-Biedl Syndrome (0.00052 vs 0.0013), allowing no conclusion about variant significance. c.1736A>G has been reported in the literature in individuals affected with Bardet-Biedl Syndrome (Stoetzel_NatGen_2006). This report does not provide unequivocal conclusions about association of the variant with Bardet-Biedl Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000029402 SCV000290895 uncertain significance Bardet-Biedl syndrome 2018-11-28 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 579 of the BBS10 protein (p.Lys579Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs141521925, ExAC 0.6%). This variant has been reported in individuals affected with Bardet-Biedl syndrome (PMID: 16582908, 24488770). To date, all reported cases were autozygous individuals in consanguineous families; in one of these families, the affected individual was also homozygous for a second BBS10 mutation (p.Lys308Phe). ClinVar contains an entry for this variant (Variation ID: 35751). Experimental studies in zebra fish have shown that this missense change results in gastrulation defects (PMID: 20498079). In summary, this variant has been observed in the homozygous state in multiple patients affected with Bardet-Biedl syndrome, and experimental data from a model organism suggests that this missense disrupts BBS10 protein function. However, this variant has also been observed in the general population at frequencies greater than expected for a pathogenic BBS10 mutation. For these reasons, this change has been classified as a Variant of Uncertain Significance.
PreventionGenetics,PreventionGenetics RCV000246690 SCV000314385 likely benign not specified criteria provided, single submitter clinical testing
Counsyl RCV000675134 SCV000800713 uncertain significance Bardet-Biedl syndrome 10 2018-05-23 criteria provided, single submitter clinical testing

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