Submissions for variant NM_001376.5(DYNC1H1):c.4395+2C>T

gnomAD frequency: 0.00035  dbSNP: rs192594531

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000194080	SCV000247210	likely benign	not specified	2016-03-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000194080	SCV000512895	benign	not specified	2016-11-03	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000460645	SCV000559780	benign	Charcot-Marie-Tooth disease axonal type 2O	2024-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002314804	SCV000848079	likely benign	Inborn genetic diseases	2018-06-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, Illumina	RCV000460645	SCV001267854	benign	Charcot-Marie-Tooth disease axonal type 2O	2017-04-28	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV001110418	SCV001267855	benign	Autosomal dominant cerebellar ataxia	2017-04-28	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001172863	SCV001335936	likely benign	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224213	SCV003919907	likely benign	Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures; Charcot-Marie-Tooth disease axonal type 2O; Intellectual disability, autosomal dominant 13	2022-09-15	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 0.8% (174/19950) (https://gnomad.broadinstitute.org/variant/14-102467693-C-T?dataset=gnomad_r2_1). This variant is present in ClinVar, with several labs classifying this variant as Likely benign or Benign (Variation ID:210869). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant alters the consensus splice sequence (+/- 1,2) which may result in an absent or abnormal protein. However, further studies are needed to understand its impact. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign.