Submissions for variant NM_001377.3(DYNC2H1):c.3097-4A>G

gnomAD frequency: 0.00476  dbSNP: rs368802969

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000176276	SCV000227906	benign	not specified	2015-02-10	criteria provided, single submitter	clinical testing
Invitae	RCV000199922	SCV000252739	benign	Jeune thoracic dystrophy	2024-01-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000176276	SCV000714437	benign	not specified	2017-03-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001286037	SCV001472555	benign	Asphyxiating thoracic dystrophy 3	2020-04-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000176276	SCV003844779	benign	not specified	2023-02-15	criteria provided, single submitter	clinical testing	Variant summary: DYNC2H1 c.3097-4A>G alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00091 in 136706 control chromosomes, predominantly at a frequency of 0.014 within the African or African-American subpopulation in the gnomAD database, including one homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in DYNC2H1 causing Short-rib thoracic dysplasia phenotype (0.0025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.3097-4A>G in individuals affected with Short-rib thoracic dysplasia and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters (evaluation after 2014) cite this variant as benign (n=4) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as benign.
Dan Cohn Lab, University Of California Los Angeles	RCV000199922	SCV000611950	pathogenic	Jeune thoracic dystrophy	2017-06-01	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000199922	SCV001479378	likely pathogenic	Jeune thoracic dystrophy		no assertion criteria provided	research