ClinVar Miner

Submissions for variant NM_024596.5(MCPH1):c.2145G>A (p.Trp715Ter)

gnomAD frequency: 0.00013  dbSNP: rs201599657
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins NTD LLC (GA) RCV000481434 SCV000338577 pathogenic not provided 2016-01-21 criteria provided, single submitter clinical testing
GeneDx RCV000481434 SCV000574384 pathogenic not provided 2017-03-28 criteria provided, single submitter clinical testing The W715X nonsense variant in the MCPH1 gene is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The W715X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Therefore, we interpret W715X as a pathogenic variant.
Genetic Services Laboratory,University of Chicago RCV000351713 SCV000595728 pathogenic Microcephaly 1, primary, autosomal recessive 2017-05-01 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV000351713 SCV000915257 uncertain significance Microcephaly 1, primary, autosomal recessive 2018-10-15 criteria provided, single submitter clinical testing This variant is a stop-gained variant, which was observed by ICSL 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 for this variant, it 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. No publications were found based on this search. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for this disease.
Invitae RCV000481434 SCV001582758 pathogenic not provided 2021-09-02 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 715 (p.Trp715*) of the MCPH1 gene. It is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in MCPH1 are known to be pathogenic (PMID: 20978018). ClinVar contains an entry for this variant (Variation ID: 285523). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001844112 SCV002103988 likely pathogenic Autosomal recessive primary microcephaly 2022-02-03 criteria provided, single submitter clinical testing Variant summary: MCPH1 c.2145G>A (p.Trp715X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00011 in 249568 control chromosomes (gnomAD). To our knowledge, no occurrence of c.2145G>A in individuals affected with Primary Autosomal Recessive Microcephaly and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant pathogenic (n=4) and VUS (n=2) . Based on the evidence outlined above, the variant was classified as likely pathogenic.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille RCV001251830 SCV001427572 uncertain significance Intellectual disability 2019-01-01 no assertion criteria provided clinical testing

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