Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003401409 | SCV004122870 | uncertain significance | not specified | 2023-10-13 | criteria provided, single submitter | clinical testing | Variant summary: DCC c.2260G>A (p.Val754Met) results in a conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 251228 control chromosomes, predominantly at a frequency of 0.0019 within the East Asian subpopulation in the gnomAD database. c.2260G>A has been reported in the literature in at least one family with heterozygous siblings affected with agenesis of the corpus callosum (ACC), normal intellectual ability, minor motor difficulties without mirror movements, and a heterozygous father with unknown ACC phenotype who was otherwise asymptomatic, all without evidence of causality (e.g. Marsh_2017). The variant allele was also reported in individuals with male infertility including idiopathic hypogonadotropic hypogonadism (e.g. Sun_2022, Capalbo_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Mirror Movements 1 or other DCC-related disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36123965, 28250454, 31589614, 35246524). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Neurogenetics Research; Murdoch Childrens Research Institute | RCV000416318 | SCV000485058 | pathogenic | Corpus callosum, agenesis of | 2016-01-01 | no assertion criteria provided | research | |
| Gene Friend Way, |
RCV003313952 | SCV004013885 | pathogenic | Autism spectrum disorder | 2023-07-28 | no assertion criteria provided | clinical testing | Carriers of this DCC Val754Met mutation in our study were diagnosed with ASD with ADHD symptoms. DCC genes play an important role in synaptic function and plasticity in the central nervous system (Keino-Masu et al. 1996), especially in the Corpus callosum. Haplotypes in DCC are associated with ASD susceptibility (Li et al., 2020). |