ClinVar Miner

Submissions for variant NM_153704.5(TMEM67):c.1322G>T (p.Arg441Leu) (rs386834183)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000823807 SCV000964677 uncertain significance Joubert syndrome; Meckel-Gruber syndrome 2018-11-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 441 of the TMEM67 protein (p.Arg441Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with Meckel-Gruber syndrome (PMID: 20232449). ClinVar contains an entry for this variant (Variation ID: 56765). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Arg441 amino acid residue in TMEM67. Other variant(s) that disrupt this residue have been observed in individuals with TMEM67-related conditions (PMID: 19574260, 23351400), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000050178 SCV000082588 probable-pathogenic Meckel syndrome type 3 no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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