Submissions for variant NM_001376.5(DYNC1H1):c.1861G>A (p.Asp621Asn)

gnomAD frequency: 0.00003  dbSNP: rs755333803

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000379272	SCV000385002	likely benign	Autosomal dominant cerebellar ataxia	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.
Illumina Laboratory Services, Illumina	RCV000703334	SCV000385003	uncertain significance	Charcot-Marie-Tooth disease axonal type 2O	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, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000703334	SCV000832231	likely benign	Charcot-Marie-Tooth disease axonal type 2O	2024-04-15	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354735	SCV001549422	uncertain significance	not provided		no assertion criteria provided	clinical testing	The DYNC1H1 p.Asp621Asn variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs755333803) and ClinVar (classified as a VUS by Illumina Clinical Services and Invitae). The variant was also identified in control databases in 7 of 251326 chromosomes at a frequency of 0.000028 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the South Asian population in 7 of 30616 chromosomes (freq: 0.000229), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish) or Other populations. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Asp621 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.