Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Eurofins Ntd Llc |
RCV000285663 | SCV000334225 | uncertain significance | not provided | 2017-11-17 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000639708 | SCV000761289 | uncertain significance | Facioscapulohumeral muscular dystrophy 2 | 2024-12-23 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1281 of the SMCHD1 protein (p.Ile1281Val). This variant is present in population databases (rs201059575, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SMCHD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 282658). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SMCHD1 protein function with a negative predictive value of 80%. 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 | RCV002518858 | SCV003714285 | uncertain significance | Inborn genetic diseases | 2022-01-04 | criteria provided, single submitter | clinical testing | The c.3841A>G (p.I1281V) alteration is located in exon 30 (coding exon 30) of the SMCHD1 gene. This alteration results from a A to G substitution at nucleotide position 3841, causing the isoleucine (I) at amino acid position 1281 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
| Department of Pathology and Laboratory Medicine, |
RCV000285663 | SCV001552277 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The SMCHD1 p.I1281V variant was not identified in the literature but was identified in dbSNP (ID: rs201059575) and ClinVar (classified as uncertain significance by EGL Genetic Diagnostics and Invitae). The variant was identified in control databases in 76 of 279258 chromosomes at a frequency of 0.0002721 (Genome Aggregation Database March 6, 2019, v2.1.1). The p.I1281 residue is not conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; however this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. 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. |