Submissions for variant NM_170784.3(MKKS):c.7C>T (p.Arg3Cys)

gnomAD frequency: 0.00004  dbSNP: rs779042065

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001228518	SCV001400919	uncertain significance	Bardet-Biedl syndrome; McKusick-Kaufman syndrome	2022-08-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 3 of the MKKS protein (p.Arg3Cys). This variant is present in population databases (rs779042065, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MKKS-related conditions. ClinVar contains an entry for this variant (Variation ID: 955812). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
GeneDx	RCV001806063	SCV002050410	uncertain significance	not provided	2021-06-30	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533)
Genetic Services Laboratory, University of Chicago	RCV001819927	SCV002071392	uncertain significance	not specified	2021-03-08	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MKKS gene demonstrated a sequence change, c.7C>T, in exon 3 that results in an amino acid change, p.Arg3Cys. This sequence change has been described in gnomAD with a population frequency of 0.0089% (dbSNP rs779042065). The p.Arg3Cys change affects a highly conserved amino acid residue located in a domain of the MKKS protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg3Cys substitution. This sequence change does not appear to have been previously described in patients with MKKS-related disorders Due to the lack of sufficient evidences, the clinical significance of the p.Arg3Cys change remains unknown at this time.
SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation	RCV003224532	SCV003920698	uncertain significance	Bardet-Biedl syndrome	2023-06-02	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV005029793	SCV005656255	uncertain significance	McKusick-Kaufman syndrome; Bardet-Biedl syndrome 6	2024-04-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004538479	SCV004120256	uncertain significance	MKKS-related disorder	2024-05-28	no assertion criteria provided	clinical testing	The MKKS c.7C>T variant is predicted to result in the amino acid substitution p.Arg3Cys. This variant was reported as a single MKKS allele in an individual from a large Bardet-Biedl syndrome cohort; however, no additional evidence was provided to support pathogenicity (Gnanasekaran et al 2023. PubMed ID: 37431782). This variant is reported in 0.016% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.