Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001043465 | SCV001207214 | pathogenic | Bardet-Biedl syndrome; McKusick-Kaufman syndrome | 2024-02-14 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 41 of the MKKS protein (p.Gly41Arg). This variant is present in population databases (rs766132697, gnomAD 0.009%). This missense change has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 20472660; Invitae). ClinVar contains an entry for this variant (Variation ID: 841278). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MKKS protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. |
| Fulgent Genetics, |
RCV002479273 | SCV002784423 | uncertain significance | McKusick-Kaufman syndrome; Bardet-Biedl syndrome 6 | 2022-03-02 | criteria provided, single submitter | clinical testing | |
| Revvity Omics, |
RCV003490024 | SCV004238283 | likely pathogenic | not provided | 2023-04-04 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV005056820 | SCV004813168 | likely pathogenic | Bardet-Biedl syndrome | 2024-11-06 | criteria provided, single submitter | clinical testing | Variant summary: MKKS c.121G>C (p.Gly41Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251080 control chromosomes. c.121G>C has been reported in the literature in individuals affected with Bardet-Biedl Syndrome, including as a homozygote and compound heterozygote genotype (e.g. Billingsley_2010, Meyer_2022, Labcorp (formerly Invitae)). These data indicate that the variant is likely to be associated with disease. 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: 20472660, 35112343). ClinVar contains an entry for this variant (Variation ID: 841278). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Prevention |
RCV004536080 | SCV004118184 | pathogenic | MKKS-related disorder | 2024-07-05 | no assertion criteria provided | clinical testing | The MKKS c.121G>C variant is predicted to result in the amino acid substitution p.Gly41Arg. This missense variant was reported in the homozygous state in an individual diagnosed with Bardet-Biedl syndrome; however, no family or functional data was presented to support the pathogenicity of this variant (Billingsley et al 2010. PubMed ID 20472660). At PreventionGenetics, we have detected this variant in the homozygous state in three individual with BBS and in the heterozygous state in an individual with BBS who also had a gene deletion in MKKS. This variant is reported in 0.0085% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Taken together, we interpret this variant as pathogenic. |