Submissions for variant NM_170784.3(MKKS):c.1363G>A (p.Glu455Lys)

gnomAD frequency: 0.00021  dbSNP: rs149626732

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001056555	SCV001221005	uncertain significance	Bardet-Biedl syndrome; McKusick-Kaufman syndrome	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 455 of the MKKS protein (p.Glu455Lys). This variant is present in population databases (rs149626732, 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: 852022). 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. 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.
Illumina Laboratory Services, Illumina	RCV001139909	SCV001300108	uncertain significance	Bardet-Biedl syndrome 6	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001139910	SCV001300109	uncertain significance	McKusick-Kaufman syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
New York Genome Center	RCV003227904	SCV003925278	uncertain significance	McKusick-Kaufman syndrome; Bardet-Biedl syndrome 6	2022-03-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003405264	SCV004113061	uncertain significance	MKKS-related condition	2023-08-05	criteria provided, single submitter	clinical testing	The MKKS c.1363G>A variant is predicted to result in the amino acid substitution p.Glu455Lys. This variant was previously reported as a variant of uncertain significance in an individual with suspected Bardet-Biedl syndrome; however, that individual was already homozygous for a pathogenic variant in BBS10 (Nasser et al. 2022. PubMed ID: 35886001, supplementary data). This variant is reported in 0.026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/20-10386245-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.