Submissions for variant NM_170784.3(MKKS):c.1161+3A>G

gnomAD frequency: 0.00036  dbSNP: rs192968747

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001066770	SCV001231790	uncertain significance	Bardet-Biedl syndrome; McKusick-Kaufman syndrome	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change falls in intron 4 of the MKKS gene. It does not directly change the encoded amino acid sequence of the MKKS protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs192968747, 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: 860468). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.
Baylor Genetics	RCV001332285	SCV001524545	uncertain significance	Bardet-Biedl syndrome 6	2020-11-05	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782637	SCV005395089	likely benign	not specified	2024-09-10	criteria provided, single submitter	clinical testing	Variant summary: MKKS c.1161+3A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.1e-05 in 1613902 control chromosomes, predominantly at a frequency of 0.0012 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in MKKS causing Bardet-Biedl Syndrome phenotype (0.00076). c.1161+3A>G has been reported in the literature in the heterozygous state in an individual with features of Bardet-Biedl Syndrome (BBS), but who did not meet the full clinical criteria for a BBS diagnosis and also carried a pathogenic variant in BBS1 which was expected to have contributed to their phenotype (Guardiola_2021). This report does not provide unequivocal conclusions about association of the variant with Bardet-Biedl Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34262361). ClinVar contains an entry for this variant (Variation ID: 860468). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004545041	SCV004798032	likely benign	MKKS-related disorder	2020-07-14	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).