Submissions for variant NM_001377.3(DYNC2H1):c.3682C>A (p.Leu1228Ile)

gnomAD frequency: 0.00189  dbSNP: rs189806840

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231556	SCV000285824	likely benign	Jeune thoracic dystrophy	2025-01-21	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000726077	SCV000341784	uncertain significance	not provided	2016-05-20	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000406282	SCV000594461	likely benign	not specified	2020-10-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000726077	SCV000729022	likely benign	not provided	2018-07-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29068549, 2687404, 23456818, 26874042, 30755392)
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV000735390	SCV000854545	uncertain significance	Clinodactyly of the 5th finger; Anomalous origin of coronary artery from the pulmonary artery; Cough		criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001106985	SCV000883761	uncertain significance	Asphyxiating thoracic dystrophy 3	2019-12-07	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV001106985	SCV001264104	uncertain significance	Asphyxiating thoracic dystrophy 3	2017-04-27	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV001106985	SCV001523626	uncertain significance	Asphyxiating thoracic dystrophy 3	2019-08-23	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000406282	SCV003929130	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing	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.
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004816439	SCV005070779	uncertain significance	Optic atrophy	2023-01-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004816438	SCV005073503	uncertain significance	Retinal dystrophy	2023-01-01	criteria provided, single submitter	clinical testing
Dan Cohn Lab, University Of California Los Angeles	RCV000231556	SCV000611918	pathogenic	Jeune thoracic dystrophy	2017-06-01	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000231556	SCV001479741	likely pathogenic	Jeune thoracic dystrophy		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000726077	SCV001550750	uncertain significance	not provided		no assertion criteria provided	clinical testing	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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000726077	SCV001798513	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000726077	SCV001951624	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000726077	SCV001973908	uncertain significance	not provided		no assertion criteria provided	clinical testing