Submissions for variant NM_001377.3(DYNC2H1):c.12909C>A (p.Phe4303Leu)

gnomAD frequency: 0.00019  dbSNP: rs191971137

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000259300	SCV000344475	uncertain significance	not provided	2016-09-08	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000322811	SCV000366893	uncertain significance	Asphyxiating thoracic dystrophy 3	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.
Illumina Laboratory Services, Illumina	RCV000377480	SCV000366894	uncertain significance	Short rib-polydactyly syndrome	2016-06-14	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000259300	SCV000885344	uncertain significance	not provided	2018-06-17	criteria provided, single submitter	clinical testing	The DYNC2H1 c.12930C>A; p.Phe4310Leu variant (rs191971137), to our knowledge, is not described in the medical literature but is reported as a variant of uncertain significance in ClinVar (Variation ID: 290002) and observed in the general population at an overall frequency of 0.01% (39/274314 alleles) in the Genome Aggregation Database. The phenylalanine at codon 4310 is highly conserved, but computational algorithms (PolyPhen-2, SIFT) predict that this variant is tolerated. Due to limited information regarding this variant, its clinical significance cannot be determined with certainty. Pathogenic variants in DYNC2H1 follow autosomal recessive and digenic recessive (with NEK1 variants) inheritance patterns and are associated with short-rib thoracic dysplasia 3 with or without polydactyly (MIM: 613091). Because no other significant variants were identified in DYNC2H1 or NEK1, even if this variant is later determined to be pathogenic, this patient would be predicted to be a carrier only; however, our analysis cannot detect variants in deep intronic or enhancer regions, so an additional pathogenic variant in these regions cannot be ruled out.
Invitae	RCV002059278	SCV002455111	likely benign	Jeune thoracic dystrophy	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002522011	SCV003699899	uncertain significance	Inborn genetic diseases	2022-06-17	criteria provided, single submitter	clinical testing	The c.12930C>A (p.F4310L) alteration is located in exon 90 (coding exon 90) of the DYNC2H1 gene. This alteration results from a C to A substitution at nucleotide position 12930, causing the phenylalanine (F) at amino acid position 4310 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.