Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001871937 | SCV002166865 | uncertain significance | Marinesco-Sjögren syndrome | 2021-08-09 | criteria provided, single submitter | clinical testing | Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. ClinVar contains an entry for this variant (Variation ID: 1050089). This sequence change replaces methionine with isoleucine at codon 216 of the SIL1 protein (p.Met216Ile). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs538181924, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with SIL1-related conditions. |
| Department of Pathology and Laboratory Medicine, |
RCV001356959 | SCV001552264 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The SIL1 p.Met216Ile variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs538181924) and in control databases in 2 of 251102 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the East Asian population in 2 of 18382 chromosomes (freq: 0.000109), but not in the African, Latino, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Other, and South Asian populations. The p.Met216 residue is conserved in mammals but not in more distantly related organisms however four out of five 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. In silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing at the variant location. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |