Submissions for variant NM_001377.3(DYNC2H1):c.8831A>G (p.Gln2944Arg)

gnomAD frequency: 0.00064  dbSNP: rs201252553

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001407252	SCV001609219	likely benign	Jeune thoracic dystrophy	2024-12-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317393	SCV004020778	uncertain significance	not specified	2023-06-23	criteria provided, single submitter	clinical testing	Variant summary: DYNC2H1 c.8831A>G (p.Gln2944Arg) results in a conservative amino acid change located in the Dynein heavy chain, coiled coil stalk domain (IPR024743) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 5' donor site. One predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00012 in 244826 control chromosomes, predominantly at a frequency of 0.0018 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in DYNC2H1 causing Short-rib thoracic dysplasia (0.00012 vs 0.0025), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.8831A>G in individuals affected with Short-rib thoracic dysplasia and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV003480883	SCV004226224	uncertain significance	not provided	2023-04-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003965700	SCV004792540	likely benign	DYNC2H1-related disorder	2022-09-13	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).