ClinVar Miner

Submissions for variant NM_153704.5(TMEM67):c.958A>T (p.Ser320Cys) (rs111619594)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725926 SCV000340550 uncertain significance not provided 2018-06-29 criteria provided, single submitter clinical testing
GeneDx RCV000725926 SCV000617746 uncertain significance not provided 2018-11-23 criteria provided, single submitter clinical testing The c.958 A>T variant is observed in 69/24,714 (0.3%) alleles from individuals of African background (Lek et al., 2016). Several in-silico splice prediction models predict that c.958 A>T creates a cryptic acceptor site which may supplant the natural acceptor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. If c.958 A>T does not effect gene splicing, it will result in an S320C missense variant. The S320C variant has been previously reported to have occurred in cis with a TMEM67 G218A variant in an individual with Bardet-Biedl syndrome (BBS), a complex multi-organ ciliopathy, who was also homozygous for the E1903X nonsense variant in the CEP290 gene (Leitch et al., 2008). Functional studies demonstrated that the S320C variant significantly impaired protein function (Leitch et al., 2008). The S320C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
GeneReviews RCV000234830 SCV000292016 uncertain significance Nephronophthisis 2016-02-10 no assertion criteria provided literature only
OMIM RCV000001444 SCV000021594 risk factor Bardet-Biedl syndrome 14, modifier of 2008-04-01 no assertion criteria provided literature only
PreventionGenetics RCV000242814 SCV000316352 benign not specified criteria provided, single submitter clinical testing

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