Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000694667 | SCV000823124 | uncertain significance | Megaconial type congenital muscular dystrophy | 2023-05-15 | criteria provided, single submitter | clinical testing | 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. Variants that disrupt 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. Experimental studies have shown that this missense change does not substantially affect CHKB function (PMID: 23945283). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 573092). This missense change has been observed in individuals with megaconial congenital muscular dystrophy (PMID: 23945283, 33712684). This variant is present in population databases (rs139818555, gnomAD 0.04%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 194 of the CHKB protein (p.Arg194Gln). This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000694667 | SCV004028915 | pathogenic | Megaconial type congenital muscular dystrophy | 2023-07-03 | criteria provided, single submitter | clinical testing | Variant summary: CHKB c.581G>A (p.Arg194Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. In addition, this variant disrupts the last nucleotide of exon 4, and therefore can affect splicing. Several computational tools predict a significant impact on normal splicing: four predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.9e-05 in 246726 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.581G>A has been reported in the literature in at least 4 homozygous individuals, including 2 siblings, affected with Megaconial Type Congenital Muscular Dystrophy (e.g., Mitsuhashi_2013, Bardhan_2021, Moore_2013 (Abstract, No PMID)). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, and results showed no damaging effect of this variant on recombinant CHKB activity (e.g., Mitsuhashi_2013), however, these results do not preclude an impact on splicing. The following publications have been ascertained in the context of this evaluation (PMID: 33712684, 23945283). One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. |