Submissions for variant NM_170784.3(MKKS):c.1553G>A (p.Arg518His)

gnomAD frequency: 0.00014  dbSNP: rs149051148

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001087733	SCV000253551	likely benign	Bardet-Biedl syndrome; McKusick-Kaufman syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000990283	SCV001141212	benign	McKusick-Kaufman syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001137687	SCV001297659	uncertain significance	Bardet-Biedl syndrome 6	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000990283	SCV001297660	uncertain significance	McKusick-Kaufman syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CeGaT Center for Human Genetics Tuebingen	RCV000782192	SCV004700462	uncertain significance	not provided	2024-01-01	criteria provided, single submitter	clinical testing	MKKS: PM2, BP4
Gharavi Laboratory, Columbia University	RCV000782192	SCV000920661	likely benign	not provided	2018-09-16	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000782192	SCV001548875	likely benign	not provided		no assertion criteria provided	clinical testing	The MKKS p.Arg518His variant was identified in 1 of 163 pedigrees with Bardet-Biedl syndrome (Beales_2001_PMID:11179009). The variant was also identified in dbSNP (ID: rs149051148), ClinVar (classified as likely benign by Invitae) and LOVD 3.0 (classified as likely benign and benign). The variant was identified in control databases in 82 of 282826 chromosomes at a frequency of 0.00029 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 14 of 19954 chromosomes (freq: 0.000702), European (non-Finnish) in 54 of 129138 chromosomes (freq: 0.000418), South Asian in 10 of 30616 chromosomes (freq: 0.000327) and Latino in 4 of 35430 chromosomes (freq: 0.000113), while the variant was not observed in the African, Ashkenazi Jewish, European (Finnish), and Other populations. Functional studies of the R518H variant show no effect on the protein compared to wildtype (Hirayama_2008_PMID:18094050; Zaghloul_2010_PMID:20498079). The p.Arg518 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Clinical Genetics, Academic Medical Center	RCV001699063	SCV001917518	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000782192	SCV001929278	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000782192	SCV001965780	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528986	SCV004106361	uncertain significance	MKKS-related disorder	2024-02-21	no assertion criteria provided	clinical testing	The MKKS c.1553G>A variant is predicted to result in the amino acid substitution p.Arg518His. This variant was reported in one patient with Bardet-Biedl syndrome (Beales et al. 2001. PubMed ID: 11179009). Functional studies suggest that the p.Arg518His variant does not increase protein degradation or solubility (Hirayama et al. 2008. PubMed ID: 18094050). In another study, the p.Arg518His variant is predicted to be benign (Zaghloul et al. 2010. PubMed ID: 20498079, reported as BBS6 p.Arg518His, Table S5). This variant is reported in 0.070% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/20-10386055-C-T). It's frequency in gnomAD is higher than expected for a pathogenic change in this gene. In ClinVar it has classifications of benign, likely benign, and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/215903/). Although we suspect that this variant may be benign, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.