Submissions for variant NM_001376.5(DYNC1H1):c.13385G>A (p.Arg4462Gln)

gnomAD frequency: 0.00016  dbSNP: rs376608392

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235870	SCV000293319	uncertain significance	not provided	2015-11-18	criteria provided, single submitter	clinical testing	The R4462Q 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. The R4462Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved, and Glutamine is observed at this position in another species. 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	RCV001040227	SCV001203788	likely benign	Charcot-Marie-Tooth disease axonal type 2O	2023-12-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002379049	SCV002690390	likely benign	Inborn genetic diseases	2020-03-19	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000235870	SCV001553522	likely benign	not provided		no assertion criteria provided	clinical testing	The DYNC1H1 p.Arg4462Gln variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs376608392) and ClinVar (classified as a VUS by GeneDx). The variant was identified in control databases in 19 of 282686 chromosomes at a frequency of 0.000067 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 5 of 24956 chromosomes (freq: 0.0002), European (non-Finnish) in 12 of 129054 chromosomes (freq: 0.000093), South Asian in 1 of 30616 chromosomes (freq: 0.000033) and Latino in 1 of 35432 chromosomes (freq: 0.000028); it was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), and Other populations. The p.Arg4462 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. The variant occurs outside of the splicing consensus sequence and only 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.