Submissions for variant NM_170784.3(MKKS):c.748G>A (p.Gly250Arg)

gnomAD frequency: 0.00001  dbSNP: rs768929313

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001236723	SCV001409458	pathogenic	Bardet-Biedl syndrome; McKusick-Kaufman syndrome	2024-01-04	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 250 of the MKKS protein (p.Gly250Arg). This variant is present in population databases (rs768929313, gnomAD 0.01%). This missense change has been observed in individual(s) with Bardet-Biedl syndrome (Bardet-Biedl syndrome). ClinVar contains an entry for this variant (Variation ID: 962801). 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 observed in individuals with MKKS-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469358	SCV002766412	pathogenic	Bardet-Biedl syndrome	2022-11-15	criteria provided, single submitter	clinical testing	Variant summary: MKKS c.748G>A (p.Gly250Arg) results in a non-conservative amino acid change in 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 1.6e-05 in 251046 control chromosomes (gnomAD). c.748G>A has been reported in the literature in multiple homozygous individuals affected with Bardet-Biedl Syndrome (e.g. Pereiro_2010, Sathya Priya_2015, Huang_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter has assessed the variant since 2014: the variant was classified as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002480776	SCV002801951	likely pathogenic	McKusick-Kaufman syndrome; Bardet-Biedl syndrome 6	2021-12-09	criteria provided, single submitter	clinical testing
GeneDx	RCV003128752	SCV003805747	uncertain significance	not provided	2022-08-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33520300, 20142850, 24400638)
SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation	RCV002469358	SCV003915890	likely pathogenic	Bardet-Biedl syndrome	2023-06-02	criteria provided, single submitter	research
Baylor Genetics	RCV003469438	SCV004192596	likely pathogenic	Bardet-Biedl syndrome 6	2024-02-19	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003128752	SCV004236357	uncertain significance	not provided	2023-02-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734065	SCV005351431	pathogenic	MKKS-related disorder	2024-08-29	no assertion criteria provided	clinical testing	The MKKS c.748G>A variant is predicted to result in the amino acid substitution p.Gly250Arg. This variant has been reported in the homozygous state in multiple individuals with Bardet-Biedl syndrome (see for example, Pereiro et al. 2010. PubMed ID: 20142850; Huang et al. 2021. PubMed ID: 33520300; Rao et al. 2023. PubMed ID: 36833331). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic.