Submissions for variant NM_170784.3(MKKS):c.110A>G (p.Tyr37Cys)

gnomAD frequency: 0.00011  dbSNP: rs74315396

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724561	SCV000229153	pathogenic	not provided	2015-02-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763444	SCV000894215	pathogenic	McKusick-Kaufman syndrome; Bardet-Biedl syndrome 6	2022-03-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000824067	SCV000964948	pathogenic	Bardet-Biedl syndrome; McKusick-Kaufman syndrome	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 37 of the MKKS protein (p.Tyr37Cys). This variant is present in population databases (rs74315396, gnomAD 0.01%). This missense change has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 10802661). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 5309). 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 95%. Experimental studies have shown that this missense change affects MKKS function (PMID: 18094050, 20498079). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001075509	SCV001241133	pathogenic	Retinal dystrophy	2018-11-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001267323	SCV001445504	pathogenic	Inborn genetic diseases	2017-11-27	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000724561	SCV001446893	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
3billion	RCV000005634	SCV002058330	pathogenic	Bardet-Biedl syndrome 6	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000005309, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 18094050, , PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.87, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000071, PM2_M). The variant has been reported to be in trans as homozygous in at least one similarly affected unrelated individual (PMID: 10973251, PM3_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222341	SCV002500759	pathogenic	Bardet-Biedl syndrome	2022-03-29	criteria provided, single submitter	clinical testing	Variant summary: MKKS c.110A>G (p.Tyr37Cys) 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 6.8e-05 in 251046 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in MKKS causing Bardet-Biedl Syndrome (6.8e-05 vs 0.00076), allowing no conclusion about variant significance. c.110A>G has been reported in the literature in multiple individuals affected with Bardet-Biedl Syndrome (e.g. Katsanis_2000, Feuillan_2011, Zaghloul_2010) and McKusick-Kaufman syndrom (e.g. Stone_2000), including homozygotes. These data indicate that the variant is very likely to be associated with disease. At least two functional studies report experimental evidence evaluating an impact on protein function and this variant results in protein rapid degradation, increased insolubility of MKKS protein and forming partially immobilized structures at the centrosome (Hirayama_2008, Zaghloul_2010). Eight ClinVar submitters have assessed the variant since 2014: all eight classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
MGZ Medical Genetics Center	RCV000005634	SCV002580124	pathogenic	Bardet-Biedl syndrome 6	2022-06-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000005634	SCV004192593	pathogenic	Bardet-Biedl syndrome 6	2024-02-23	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000724561	SCV005199130	pathogenic	not provided	2023-07-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000724561	SCV005396208	likely pathogenic	not provided	2024-05-08	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (PMID: 18094050, 20498079); Identified in patients with MKKS-related ciliopathy referred for genetic testing at GeneDx and in published literature (PMID: 35886001, 10973251, 20177705, 25982971, 10802661); 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: 10802661, 18094050, 22446187, 20177705, 25982971, 11673413, 21044901, 12107442, 34426522, 34929400, 20498079, 35112343, 10973251, 35886001, 31964843)
OMIM	RCV000005633	SCV000025815	pathogenic	McKusick-Kaufman syndrome	2001-09-21	no assertion criteria provided	literature only
OMIM	RCV000005634	SCV000025816	pathogenic	Bardet-Biedl syndrome 6	2001-09-21	no assertion criteria provided	literature only
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV001328206	SCV001449355	pathogenic	Nephronophthisis	2016-07-26	no assertion criteria provided	clinical testing	This patient is heterozygous for the c.110A>G p.(Tyr37Cys) variant in the MKKS gene. This variant is listed in the ExAC database (http://exac.broadinstitute.org) with a very low allele frequency of 0.0058% (27 out of 121,342 alleles). It has been reported in the homozygous state in a patient with Bardet-Biedl syndrome (Bardet-Biedl syndrome) and in a compound heterozygous state with a patient with McKusick-Kaufman syndrome (Katsanis et al. 2000 Nat Genet 26: 67-70; Stone et al. 2000 Nat Genet 25: 79-82). In vitro studies found that the p.Tyr37Cys substitution led to decreased protein levels and resulted in structual instability (Hirayama et al. 2008 Mol Biol Cell 19: 899-911). This variant is considered to be pathogenic according to the ACMG guidelines.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000724561	SCV001809485	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000724561	SCV001921416	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000724561	SCV001932084	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000724561	SCV001951484	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532292	SCV004107387	pathogenic	MKKS-related disorder	2024-06-25	no assertion criteria provided	clinical testing	The MKKS c.110A>G variant is predicted to result in the amino acid substitution p.Tyr37Cys. This variant has been reported to be causative for Bardet-Biedl syndrome and McKusick-Kaufman syndrome (Katsanis et al. 2001. PubMed ID: 11567139; Stone et al. 2000. PubMed ID: 10802661; Muller et al. 2010. PubMed ID: 20177705; Zaghloul et al. 2010. PubMed ID: 20498079; Scheidecker et al. 2015. PubMed ID: 25982971). This variant is reported in 0.014% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.