Submissions for variant NM_017777.4(MKS1):c.763G>C (p.Gly255Arg)

dbSNP: rs201237547

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657869	SCV000779629	uncertain significance	not provided	2018-05-16	criteria provided, single submitter	clinical testing	The G255R variant in the MKS1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The G255R variant is observed in 21/30,782 (0.0682%) alleles from individuals of South Asian background in large population cohorts (Lek et al., 2016). The G255R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret G255R as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000695711	SCV000824226	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 255 of the MKS1 protein (p.Gly255Arg). This variant is present in population databases (rs201237547, gnomAD 0.07%), including at least one homozygous and/or hemizygous individual. 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: 546082). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MKS1 protein function. 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.
Pars Genome Lab	RCV001526426	SCV001736811	uncertain significance	Bardet-Biedl syndrome 13	2021-05-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001526426	SCV001806004	uncertain significance	Bardet-Biedl syndrome 13	2021-07-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001578717	SCV001806005	uncertain significance	Joubert syndrome 28	2021-07-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001272928	SCV001806006	uncertain significance	Meckel syndrome, type 1	2021-07-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004533438	SCV004120581	uncertain significance	MKS1-related disorder	2023-04-04	criteria provided, single submitter	clinical testing	The MKS1 c.763G>C variant is predicted to result in the amino acid substitution p.Gly255Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.069% of alleles in individuals of South Asian descent in gnomAD, including one homozygote (http://gnomad.broadinstitute.org/variant/17-56290438-C-G). Although we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc.	RCV001272928	SCV001455378	uncertain significance	Meckel syndrome, type 1	2020-09-16	no assertion criteria provided	clinical testing