Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular 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. |
| Invitae | RCV001379590 | SCV001577416 | likely pathogenic | not provided | 2024-01-18 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 339 of the TMEM5 protein (p.Tyr339Cys). This variant is present in population databases (rs150736997, gnomAD 0.004%). This missense change has been observed in individuals with severe dystroglycanopathy (PMID: 23217329). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39604). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TMEM5 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TMEM5 function (PMID: 27733679). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Neuberg Supratech Reference Laboratories Pvt Ltd, |
RCV000032804 | SCV002073323 | pathogenic | Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 10 | criteria provided, single submitter | clinical testing | The missense variant p.Y339C in RXYLT1 (NM_014254.3) has been reported in homozygous and compound heterozygous state in affected patients (Vuillaumier-Barrot et al). Functional studies have depicted a damaging effect. The variant has been submitted to ClinVar with conflicting interpretations of pathogenicity: Pathogenic and VUS. The p.Y339C variant is observed in 4/1,13,374 (0.0035%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.Y339C missense variant is predicted to be damaging by both SIFT and PolyPhen2. The tyrosine residue at codon 339 of RXYLT1 is conserved in all mammalian species. The nucleotide c.1016 in RXYLT1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as 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 |