Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000797066 | SCV000936606 | uncertain significance | Focal segmental glomerulosclerosis 5; Charcot-Marie-Tooth disease dominant intermediate E | 2019-07-30 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine with alanine at codon 830 of the INF2 protein (p.Gly830Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant also falls at the last nucleotide of exon 16 of the INF2 coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs377340315, ExAC 0.002%). 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with INF2-related conditions. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV003987708 | SCV004803902 | uncertain significance | not specified | 2024-01-19 | criteria provided, single submitter | clinical testing | Variant summary: INF2 c.2489G>C (p.Gly830Ala) results in a non-conservative amino acid change located in the Formin, FH2 domain (IPR015425) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 245590 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2489G>C in individuals affected with Charcot-Marie Disease, Dominant Intermediate E and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 643380). Based on the evidence outlined above, the variant was classified as uncertain significance. |