ClinVar Miner

Submissions for variant NM_001165927.1(MKS1):c.88C>T (p.His30Tyr) (rs199832333)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724912 SCV000332374 uncertain significance not provided 2018-06-05 criteria provided, single submitter clinical testing
GeneDx RCV000724912 SCV000590207 uncertain significance not provided 2017-06-15 criteria provided, single submitter clinical testing The H40Y variant in the MKS1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The H40Y variant is observed in 46/66736 (0.07%) alleles from individuals of non-Finnish European background, in the ExAC dataset (Lek et al., 2016). The H40Y 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. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret H40Y as a variant of uncertain significance.
Fulgent Genetics,Fulgent Genetics RCV000765374 SCV000896640 uncertain significance Bardet-Biedl syndrome 13; Meckel syndrome type 1; Joubert syndrome 28 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV001062255 SCV001227040 uncertain significance Joubert syndrome; Meckel-Gruber syndrome 2020-01-08 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 40 of the MKS1 protein (p.His40Tyr). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs199832333, ExAC 0.07%). This variant has not been reported in the literature in individuals with MKS1-related disease. ClinVar contains an entry for this variant (Variation ID: 281544). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.

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