ClinVar Miner

Submissions for variant NM_024596.5(MCPH1):c.1351G>A (p.Glu451Lys) (rs202004426)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV001172454 SCV000193538 benign not specified 2017-09-18 criteria provided, single submitter clinical testing
GeneDx RCV000498490 SCV000589453 uncertain significance not provided 2015-07-23 criteria provided, single submitter clinical testing The E451K variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The 1000 Genomes Project reports E451K was observed in 18/978 (1.84%) alleles from individuals of South Asian background, indicating it may be a rare (benign) variant in this population. The E451K 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. However, this substitution occurs at a position that is not conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the E451K variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or a rare benign variant.
Illumina Clinical Services Laboratory,Illumina RCV000146273 SCV001321855 likely benign Primary autosomal recessive microcephaly 1 2018-01-13 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

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