ClinVar Miner

Submissions for variant NM_014254.3(RXYLT1):c.1016A>G (p.Tyr339Cys) (rs150736997)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000032804 SCV000813233 uncertain significance Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 10 2018-05-11 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 339 of the TMEM5 protein (p.Tyr339Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs150736997, ExAC 0.004%). This variant has been observed as homozygous to segregate with severe dystroglycanopathy in a family, and has also been observed in combination with another TMEM5 variant in an individual affected with severe dystroglycanopathy (PMID: 23217329). ClinVar contains an entry for this variant (Variation ID: 39604). Experimental studies have shown that this missense change disrupts the function of the TMEM5 protein (PMID: 27733679). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000611814 SCV000711748 likely pathogenic Walker-Warburg congenital muscular dystrophy 2015-12-17 criteria provided, single submitter clinical testing The p.Tyr339Cys variant in TMEM5 has been reported in two families with cobblest one lissencephaly. In one family two affected fetuses were homozygous and in the second family the affected fetus was compound heterozygous for this variant (V uillaumier-Barrot 2012). This variant has been identified in 3/66734 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitu te.org; dbSNP rs150736997). Although it has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency . Computational prediction tools and conservation analysis suggest that the p.Ty r339Cys variant may impact the protein, though this information is not predictiv e enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Tyr339Cys variant is likely pathogenic.
OMIM RCV000032804 SCV000056572 pathogenic Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 10 2012-12-07 no assertion criteria provided literature only

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