Submissions for variant NM_170784.3(MKKS):c.463C>T (p.Arg155Cys)

gnomAD frequency: 0.00004  dbSNP: rs755050269

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000335481	SCV000432771	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	RCV000391079	SCV000432772	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001865227	SCV002115325	uncertain significance	Bardet-Biedl syndrome; McKusick-Kaufman syndrome	2022-09-19	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 155 of the MKKS protein (p.Arg155Cys). This variant is present in population databases (rs755050269, gnomAD 0.03%). 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: 337692). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Ambry Genetics	RCV002519998	SCV003681783	uncertain significance	Inborn genetic diseases	2021-02-26	criteria provided, single submitter	clinical testing	The c.463C>T (p.R155C) alteration is located in exon 3 (coding exon 1) of the MKKS gene. This alteration results from a C to T substitution at nucleotide position 463, causing the arginine (R) at amino acid position 155 to be replaced by a cysteine (C). The p.R155C alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV003225062	SCV003921419	uncertain significance	not provided	2022-10-28	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
PreventionGenetics, part of Exact Sciences	RCV004530376	SCV004116123	uncertain significance	MKKS-related disorder	2022-10-19	criteria provided, single submitter	clinical testing	The MKKS c.463C>T variant is predicted to result in the amino acid substitution p.Arg155Cys. To our knowledge, this variant has not been reported in the literature. Of note, a different missense variant affecting the same amino acid has been reported in the heterozygous state in an individual with Bardet-Biedl syndrome (c.464G>T; p.Arg155Leu; Slavotinek et al. 2002. PubMed ID: 12107442; Zaghloul et al. 2010. PubMed ID: 20498079). In addition, functional studies of the p.Arg155Leu variant have shown decreased protein function compared to the wild-type protein (Hirayama et al. 2008. PubMed ID: 18094050). However, at this time, the clinical significance of the c.463C>T (p.Arg155Cys) variant is uncertain due to the absence of conclusive functional and genetic evidence.