ClinVar Miner

Submissions for variant NM_001165927.1(MKS1):c.514G>A (p.Val172Ile) (rs200185068)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000226628 SCV000290336 uncertain significance Joubert syndrome; Meckel-Gruber syndrome 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 182 of the MKS1 protein (p.Val182Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs200185068, ExAC 0.1%). This variant has not been reported in the literature in individuals with MKS1-related disease. ClinVar contains an entry for this variant (Variation ID: 241188). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
GeneDx RCV000728102 SCV000618197 uncertain significance not provided 2017-09-10 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MKS1 gene. The V182I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V182I variant is observed in 13/11568 (0.11%) alleles from individuals of Latino background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. The V182I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000728102 SCV000855635 uncertain significance not provided 2018-01-30 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765372 SCV000896638 uncertain significance Bardet-Biedl syndrome 13; Meckel syndrome type 1; Joubert syndrome 28 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001122692 SCV001281438 uncertain significance Bardet-Biedl syndrome 13 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV001122693 SCV001281439 uncertain significance Meckel syndrome type 1 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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