ClinVar Miner

Submissions for variant NM_014254.3(RXYLT1):c.1018C>T (p.Arg340Ter)

gnomAD frequency: 0.00001  dbSNP: rs397514695
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002514180 SCV003297891 pathogenic not provided 2024-01-04 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg340*) in the RXYLT1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 104 amino acid(s) of the RXYLT1 protein. This variant is present in population databases (rs397514695, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Walker-Warburg syndrome (PMID: 23519211). ClinVar contains an entry for this variant (Variation ID: 50606). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects RXYLT1 function (PMID: 23519211). This variant disrupts a region of the RXYLT1 protein in which other variant(s) (p.Asp355Valfs*33) have been determined to be pathogenic (PMID: 23217329). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV004017340 SCV004847937 pathogenic Walker-Warburg congenital muscular dystrophy 2015-02-06 criteria provided, single submitter clinical testing The p.Arg340X variant in TMEM5 has been reported in homozygosity in 1 individual with clinical features of Walker-Warburg syndrome (Jae 2013). This variant has been identified in 2/66,736 (~0%) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397514695). This nonsense variant leads to a premature termination codon at position 340. This alteration occurs within the last exon and is most likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In vitro functional studies provide some evidence that the p.Arg340X variant may impact protein function (Jae 2013). In addition, the absence of over 100 amino acids from the protein is likely to impact its stability and/or function. Homozygous or compound heterozygous loss of function of TMEM5 has been shown to cause congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies. In summary, this variant meets our criteria to be classified as pathogenic for dystroglycanopathy in an autosomal recessive manner.
OMIM RCV000043551 SCV000071328 pathogenic Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 10 2013-04-26 no assertion criteria provided literature only

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