Submissions for variant NM_001376.5(DYNC1H1):c.13855A>G (p.Ile4619Val)

dbSNP: rs879254286

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236243	SCV000294064	uncertain significance	not provided	2017-02-20	criteria provided, single submitter	clinical testing	The I4619V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species. However, the I4619V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000558294	SCV000651621	likely benign	Charcot-Marie-Tooth disease axonal type 2O	2023-12-01	criteria provided, single submitter	clinical testing
New York Genome Center	RCV002274953	SCV002564167	uncertain significance	Intellectual disability, autosomal dominant 13	2021-08-27	criteria provided, single submitter	clinical testing	The c.13855A>G (p.Ile4619Val) variant identified in the DYNC1H1 gene substitutes a very well conserved Isoleucine for Valine at amino acid 4619/4647 (exon 78/78). This variant is found with low frequency in gnomAD(v2.1.1)(1 heterozygote, 0 homozygotes; allele frequency: 3.98e-6) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score:0.007) and Benign(REVEL; score:0.2849) to the function of the canonical transcript. This variant is reported in ClinVar as a Variant of Uncertain Significance (VarID:246487), and to our current knowledge has not been reported in affected individuals in the literature. The p.Ile4619 residue is not within a mapped domain of DYNC1H1(UniProtKB:Q14204). Given the lack of compelling evidence for its pathogenicity, the c.13855A>G (p.Ile4619Val) variant identified in the DYNC1H1 gene is reported as a Variant of Uncertain Significance.