Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001039456 | SCV001202986 | uncertain significance | Joubert syndrome 16 | 2022-09-07 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 139 of the TMEM138 protein (p.Val139Ile). This variant is present in population databases (rs141029883, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with TMEM138-related conditions. ClinVar contains an entry for this variant (Variation ID: 837999). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. |
| Ambry Genetics | RCV002553058 | SCV003641530 | likely benign | Inborn genetic diseases | 2022-09-14 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
| Department of Pathology and Laboratory Medicine, |
RCV001357922 | SCV001553526 | likely benign | not provided | no assertion criteria provided | clinical testing | The TMEM138 p.Val139Ile variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs141029883) and LOVD 3.0 (variant effect not shared). The variant was identified in control databases in 5 of 251314 chromosomes at a frequency of 0.0000199 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 1 of 6136 chromosomes (freq: 0.000163), African in 1 of 16248 chromosomes (freq: 0.000062), East Asian in 1 of 18394 chromosomes (freq: 0.000054), South Asian in 1 of 30612 chromosomes (freq: 0.000033) and European (non-Finnish) in 1 of 113724 chromosomes (freq: 0.000009), but was not observed in the Latino, Ashkenazi Jewish, or European (Finnish) populations. The p.Val139 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. |