ClinVar Genomic variation as it relates to human health

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

The DYNC2H1 c.3682C>A; p.Leu1228Ile variant (rs189806840) is reported in the literature in individuals affected with asphyxiating thoracic dysplasia, several of whom carried additional variants in the DYNC2H1 gene (Cossu 2016, Schmidts 2013, Zhang 2018). The p.Leu1228Ile variant is found in the Latino population with an overall allele frequency of 0.30% (104/35140 alleles) in the Genome Aggregation Database, and it is reported in ClinVar (Variation ID: 238270). The leucine at codon 1228 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, due to limited information, the clinical significance of the p.Leu1228Ile variant is uncertain at this time. References: Cossu C et al. New mutations in DYNC2H1 and WDR60 genes revealed by whole-exome sequencing in two unrelated Sardinian families with Jeune asphyxiating thoracic dystrophy. Clin Chim Acta. 2016 Apr 1;455:172-80. Schmidts M et al. Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement. J Med Genet. 2013 May;50(5):309-23. Zhang W et al. Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat. 2018 Jan;39(1):152-166.

This variant is associated with the following publications: (PMID: 29068549, 2687404, 23456818, 26874042, 30755392)

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

Variant summary: DYNC2H1 c.3682C>A (p.Leu1228Ile) results in a conservative amino acid change located in the Dynein heavy chain, linker region (IPR013602) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 247758 control chromosomes, predominantly at a frequency of 0.0028 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.12 fold of the estimated maximal expected allele frequency for a pathogenic variant in DYNC2H1 causing Short-rib thoracic dysplasia phenotype (0.0025). c.3682C>A has been reported in the literature in individuals affected with features of Short-rib thoracic dysplasia/Asphyxiating thoracic dystrophy (Zhang_2018, Schmitds_2013, Cossu_2016, Cloney_2022), and some of these individuals had a (likely) pathogenic variants in trans, although in another case additional variants in the DYNC2H1 gene were also noted. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29068549, 34740920, 26874042, 23456818). ClinVar contains an entry for this variant (Variation ID: 238270). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

The DYNC2H1 p.Leu1228Ile variant was identified in 4 of 446 proband chromosomes (frequency: 0.00897) from individuals or families with short-rib polydactyly syndromes (SRPS), asphyxiating thoracic dystrophy (ATD) or Ellis van Creveld (EVC) syndrome (Schmidts_2013_PMID:23456818; Zhang_2018_PMID:29068549). The variant was also identified in dbSNP (ID: rs189806840), ClinVar (classified as likely benign by Invitae and GeneDx, a VUS by 4 labs and pathogenic by Dan Cohn Lab,University Of California Los Angeles) and LOVD 3.0. The variant was not identified in Cosmic. The variant was identified in control databases in 442 of 279018 chromosomes at a frequency of 0.001584 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 21 of 7080 chromosomes (freq: 0.002966), Latino in 104 of 35140 chromosomes (freq: 0.00296), European (non-Finnish) in 290 of 127576 chromosomes (freq: 0.002273), African in 22 of 24080 chromosomes (freq: 0.000914), European (Finnish) in 4 of 24956 chromosomes (freq: 0.00016) and Ashkenazi Jewish in 1 of 10318 chromosomes (freq: 0.000097), while the variant was not observed in the East Asian and South Asian populations. The p.Leu1228 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.