Submissions for variant NM_170784.3(MKKS):c.749G>A (p.Gly250Glu)

gnomAD frequency: 0.00003  dbSNP: rs972466774

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000804082	SCV000943976	likely pathogenic	Bardet-Biedl syndrome; McKusick-Kaufman syndrome	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 250 of the MKKS protein (p.Gly250Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Bardet-Biedl syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 649204). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MKKS protein function. This variant disrupts the p.Gly250 amino acid residue in MKKS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20142850, 24400638; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004538100	SCV004115312	uncertain significance	MKKS-related disorder	2022-11-08	criteria provided, single submitter	clinical testing	The MKKS c.749G>A variant is predicted to result in the amino acid substitution p.Gly250Glu. In vitro RNA analysis of this variant found that it was not associated with an effect on splicing (Wai et al. 2020. PubMed ID: 32123317, Variant Summary). Alternate nucleotide changes affecting the same amino acid (c.748G>A; Gly250Arg) have been previously reported in the homozygous state in individuals with Bardet-Biedl syndrome (see for example Pereiro et al. 2010. PubMed ID: 20142850; Sathya Priya et al. 2015. PubMed ID: 24400638). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/20-10393414-C-T). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.