Submissions for variant NM_170784.3(MKKS):c.724G>T (p.Ala242Ser)

gnomAD frequency: 0.00508  dbSNP: rs74315394

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000153503	SCV000203023	likely benign	not specified	2018-04-18	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000436285	SCV000511404	likely benign	not provided	2017-01-25	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084541	SCV000636916	benign	Bardet-Biedl syndrome; McKusick-Kaufman syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000990285	SCV001141215	benign	McKusick-Kaufman syndrome	2023-08-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000990285	SCV001303013	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.
Genetic Services Laboratory, University of Chicago	RCV000153503	SCV002066037	likely benign	not specified	2020-01-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000153503	SCV002512012	likely benign	not specified	2022-03-08	criteria provided, single submitter	clinical testing	Variant summary: MKKS c.724G>T (p.Ala242Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0052 in 251040 control chromosomes in the gnomAD database, including 10 homozygotes. The observed variant frequency is approximately 6.9 fold of the estimated maximal expected allele frequency for a pathogenic variant in MKKS causing Bardet-Biedl Syndrome phenotype (0.00076), strongly suggesting that the variant is benign. Although reported in the literature, to our knowledge, no penetrant association of c.724G>T in individuals affected with Bardet-Biedl Syndrome/McKusick-Kaufman syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments and a majority consensus as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000436285	SCV004149870	benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	MKKS: BS1, BS2
Mayo Clinic Laboratories, Mayo Clinic	RCV000436285	SCV004225462	uncertain significance	not provided	2023-02-17	criteria provided, single submitter	clinical testing	BS2, PS3_moderate
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000436285	SCV001808481	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000153503	SCV001920207	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000436285	SCV001928204	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000436285	SCV001974316	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000436285	SCV002036818	likely benign	not provided		no assertion criteria provided	clinical testing