Submissions for variant NM_017777.4(MKS1):c.1349T>C (p.Ile450Thr)

gnomAD frequency: 0.00157  dbSNP: rs200865108

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000280753	SCV000331448	uncertain significance	not provided	2018-07-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001087577	SCV001003391	likely benign	Familial aplasia of the vermis; Meckel-Gruber syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001122598	SCV001281326	uncertain significance	Bardet-Biedl syndrome 13	2017-04-28	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.
Illumina Laboratory Services, Illumina	RCV001128316	SCV001287743	uncertain significance	Meckel syndrome, type 1	2017-04-28	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.
Baylor Genetics	RCV001122598	SCV001520286	uncertain significance	Bardet-Biedl syndrome 13	2019-03-15	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV000280753	SCV001803267	uncertain significance	not provided	2024-08-12	criteria provided, single submitter	clinical testing	Has been reported in a patient with features of BBS as a single heterozygous variant (PMID: 18327255); Has also been reported in a patient from a cohort of patients with inherited retinal disease, potentially with a second variant; however segregation data and specific clinical information was not clearly delineated in this report (PMID: 31456290); Published functional studies demonstrate a damaging effect (PMID: 18327255); 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: 34426522, 34573333, 18327255, 31456290, 30793526)
Genome-Nilou Lab	RCV001122598	SCV001806058	uncertain significance	Bardet-Biedl syndrome 13	2021-07-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001578757	SCV001806059	uncertain significance	Joubert syndrome 28	2021-07-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001128316	SCV001806060	uncertain significance	Meckel syndrome, type 1	2021-07-14	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001820804	SCV002072159	uncertain significance	not specified	2019-12-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001820804	SCV002570899	likely benign	not specified	2022-07-01	criteria provided, single submitter	clinical testing	Variant summary: MKS1 c.1349T>C (p.Ile450Thr) 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 0.00042 in 249558 control chromosomes, predominantly at a frequency of 0.0036 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in MKS1 causing Meckel Syndrome Type 1 phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1349T>C has been reported in the literature in at least one heterozygous individual affected with Bardet-Biedl syndrome (e.g. Leitch_2008), but to our knowledge has not been found in individuals with Meckel Syndrome Type 1. Multiple assessments for this variant have been submitted to ClinVar after 2014 with conflicting assessments (likely pathogenic n=1, VUS n=6, likely benign n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Revvity Omics, Revvity	RCV000280753	SCV003808822	uncertain significance	not provided	2019-11-25	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000280753	SCV005412789	uncertain significance	not provided	2024-04-03	criteria provided, single submitter	clinical testing	BS1, PP3
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001003078	SCV001161137	likely pathogenic	Bardet-Biedl syndrome	2019-06-23	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004542971	SCV004799070	likely benign	MKS1-related disorder	2020-01-13	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).