Submissions for variant NM_017777.4(MKS1):c.190+2T>C

gnomAD frequency: 0.00004  dbSNP: rs375170572

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000665861	SCV000790052	likely pathogenic	Bardet-Biedl syndrome 13; Meckel syndrome, type 1; Joubert syndrome 28	2017-03-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000800425	SCV000940140	likely pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 2 of the MKS1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MKS1 are known to be pathogenic (PMID: 19466712, 24886560, 26490104). This variant is present in population databases (rs375170572, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with MKS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 550954). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Genome-Nilou Lab	RCV001580533	SCV001810500	likely pathogenic	Joubert syndrome 28	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001784235	SCV002023474	likely pathogenic	not provided	2021-04-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001274929	SCV002766403	likely pathogenic	Meckel syndrome, type 1	2022-11-04	criteria provided, single submitter	clinical testing	Variant summary: MKS1 c.190+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. One computational tool predicts a significant impact on normal splicing by abolishing a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.2e-05 in 249570 control chromosomes (gnomAD). To our knowledge, no occurrence of c.190+2T>C in individuals affected with Meckel Syndrome Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000665861	SCV002790645	likely pathogenic	Bardet-Biedl syndrome 13; Meckel syndrome, type 1; Joubert syndrome 28	2022-02-04	criteria provided, single submitter	clinical testing
GeneDx	RCV001784235	SCV003845932	likely pathogenic	not provided	2022-09-19	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Baylor Genetics	RCV003472074	SCV004194932	likely pathogenic	Bardet-Biedl syndrome 13	2024-03-23	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001274929	SCV001459491	likely pathogenic	Meckel syndrome, type 1	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732989	SCV005356607	likely pathogenic	MKS1-related disorder	2024-09-19	no assertion criteria provided	clinical testing	The MKS1 c.190+2T>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature in individuals with MKS1-related disorders. This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD. Variants that disrupt the consensus splice donor site in MKS1 are expected to be pathogenic. This variant is interpreted as likely pathogenic.