Submissions for variant NM_017777.4(MKS1):c.857A>G (p.Asp286Gly)

gnomAD frequency: 0.00083  dbSNP: rs151023718

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514949	SCV000610371	uncertain significance	not provided	2017-09-11	criteria provided, single submitter	clinical testing
Counsyl	RCV000664898	SCV000788928	uncertain significance	Bardet-Biedl syndrome 13; Meckel syndrome, type 1; Joubert syndrome 28	2017-01-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690393	SCV000818077	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome	2022-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 286 of the MKS1 protein (p.Asp286Gly). This variant is present in population databases (rs151023718, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with ciliopathies (PMID: 18327255, 21068128, 21258341, 28224992). ClinVar contains an entry for this variant (Variation ID: 445724). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects MKS1 function (PMID: 18327255). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Eurofins Ntd Llc (ga)	RCV000514949	SCV000854879	uncertain significance	not provided	2018-05-08	criteria provided, single submitter	clinical testing
Mendelics	RCV000989953	SCV001140699	uncertain significance	Bardet-Biedl syndrome 13	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001126360	SCV001285541	uncertain significance	Meckel syndrome, type 1	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000989953	SCV001285542	uncertain significance	Bardet-Biedl syndrome 13	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.
GeneDx	RCV000514949	SCV001822451	uncertain significance	not provided	2023-05-15	criteria provided, single submitter	clinical testing	Reported in the heterozygous state in patients with nephronophthisis, Bardet-Biedl syndrome, and a developmental eye defect with no second MKS1 variant reported (Leitch et al., 2008; Otto et al., 2011; Haer-Wigman et al., 2017); Reported in the heterozygous state in a patient with Bardet-Biedl who was also heterozygous for a variant in the RPGRIP1L gene (Khanna et al., 2009); Functional studies indicate this variant has a moderate effect on protein function and is a hypomorphic variant (Leitch et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25966130, 19430481, 28224992, 21068128, 21258341, 30718709, 31139930, 18327255, 34426522, 34573333, 32483926)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271519	SCV002555728	uncertain significance	not specified	2022-06-07	criteria provided, single submitter	clinical testing	Variant summary: MKS1 c.857A>G (p.Asp286Gly) results in a non-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 0.00051 in 249582 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MKS1 causing Meckel Syndrome Type 1 (0.00051 vs 0.0011), allowing no conclusion about variant significance. c.857A>G has been reported in the literature in individuals affected with Meckel Syndrome Type 1 or related disorders. These reports do not provide unequivocal conclusions about association of the variant with Meckel Syndrome Type 1. At least one publication reports experimental evidence evaluating an impact on protein function and suggested that this variant was hypomorphic (Leitch_2008). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely pathogenic n=1, VUS n=8). Based on the evidence outlined above, the variant was classified as uncertain significance.
New York Genome Center	RCV000664898	SCV002764340	uncertain significance	Bardet-Biedl syndrome 13; Meckel syndrome, type 1; Joubert syndrome 28	2021-09-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000664898	SCV002786590	uncertain significance	Bardet-Biedl syndrome 13; Meckel syndrome, type 1; Joubert syndrome 28	2022-02-17	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004527618	SCV004107145	uncertain significance	MKS1-related disorder	2024-03-01	criteria provided, single submitter	clinical testing	The MKS1 c.857A>G variant is predicted to result in the amino acid substitution p.Asp286Gly. This variant has previously been identified in several individuals affected with ciliopathies (Leitch et al. 2008. PubMed ID: 18327255; Otto et al. 2010. PubMed ID: 21068128; Davis et al. 2011. PubMed ID: 21258341; Haer-Wigman et al. 2017. PubMed ID: 28224992; Table S5, Martin-Merida et al. 2019. PubMed ID: 30902645). However, a second likely causative variant was not found in MKS1 in these cases. Mutant rescue experiments in zebrafish embryos with p.Asp286Gly resulted in only partial rescue, suggesting that this variant is a hypomorph in this artificial system (Leitch et al. 2008. PubMed ID: 18327255). However, the clinical significance of this rescue experiment is unclear. Splice-site prediction programs suggest that the c.857A>G variant may interfere with normal splicing (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). This variant is reported in 0.099% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Breakthrough Genomics, Breakthrough Genomics	RCV000514949	SCV005192977	uncertain significance	not provided		criteria provided, single submitter	not provided
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000514949	SCV000926866	likely pathogenic	not provided	2018-04-01	no assertion criteria provided	research
Natera, Inc.	RCV001126360	SCV001455376	uncertain significance	Meckel syndrome, type 1	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000514949	SCV001553176	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MKS1 p.Asp83Gly variant was identified in multiple individuals with ciliopathies or neural tube defects as a heterozygous variant, however a second pathogenic variant was not found in these cases (Renard_2019_PMID:31139930, Davis_2011_PMID:21258341, Otto_2011_PMID:21068128). A functional study conducted on this variant suggested this variant may impact protein function (Leitch_2008_PMID:18327255). The variant was identified in dbSNP (ID: rs151023718) and ClinVar (classified as uncertain significance by Invitae, Counsyl, and three other laboratories, and as as likely pathogenic by Medical Genetics Laboratory, Kennedy Center, Juliane Marie Center, Rigshospitalet). The variant was identified in control databases in 144 of 280976 chromosomes at a frequency of 0.0005125 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 128 of 128714 chromosomes (freq: 0.000995), Other in 3 of 7152 chromosomes (freq: 0.00042), African in 6 of 24200 chromosomes (freq: 0.000248), European (Finnish) in 4 of 25036 chromosomes (freq: 0.00016), Ashkenazi Jewish in 1 of 10362 chromosomes (freq: 0.000097) and Latino in 2 of 35376 chromosomes (freq: 0.000057), but was not observed in the East Asian or South Asian populations. The p.Asp83 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The p.Asp83Gly variant occurs in the second last base of the exon; this position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In addition, 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing and the loss of the canonical 5' splice site. However, this has not been confirmed by RNA analysis and is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Genetic Services Laboratory, University of Chicago	RCV002271519	SCV003839718	uncertain significance	not specified	2022-12-02	no assertion criteria provided	clinical testing	DNA sequence analysis of the MKS1 gene demonstrated a sequence change, c.857A>G, in exon 8 that results in an amino acid change, p.Asp286Gly. This sequence change does not appear to have been previously described in individuals with nephronophthisis, Bardet-Biedl syndrome, Leber Congenital Amaurosis and a developmental eye defect (PMID:18327255,27353947,28224992,19430481). Experimental studies indicate this variant has a moderate effect on protein function (PMID:18327255). This sequence change has been described in the gnomAD database with a frequency of 0.09% in the European subpopulation (dbSNP rs151023718). The p.Asp286Gly change affects a highly conserved amino acid residue located in a domain of the MKS1 protein that is not known to be functional. The p.Asp286Gly substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Asp286Gly change remains unknown at this time.