Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000362048 | SCV000427845 | uncertain significance | 3M syndrome 2 | 2018-01-13 | criteria provided, single submitter | clinical testing | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. |
| Invitae | RCV000893205 | SCV001037123 | likely benign | not provided | 2024-01-29 | criteria provided, single submitter | clinical testing | |
| Ce |
RCV000893205 | SCV001153337 | uncertain significance | not provided | 2019-02-01 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003401356 | SCV004122080 | uncertain significance | not specified | 2023-10-24 | criteria provided, single submitter | clinical testing | Variant summary: OBSL1 c.1255C>T (p.Arg419Cys) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 247370 control chromosomes, predominantly at a frequency of 0.0026 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.33 fold of the estimated maximal expected allele frequency for a pathogenic variant in OBSL1 causing Three M Syndrome 2 phenotype (0.0011), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1255C>T has been reported in the literature in settings of whole exome sequencing, however, not in association with a Three M syndrome phenotype (e.g. Allred_2023, Iglesias_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Three M Syndrome 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36999085, 33919104). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=2) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. |