Submissions for variant NM_001377.3(DYNC2H1):c.6551A>T (p.Asp2184Val)

gnomAD frequency: 0.00101  dbSNP: rs201967064

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000365728	SCV000332741	likely benign	not specified	2015-07-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001078688	SCV000755491	likely benign	Jeune thoracic dystrophy	2025-01-15	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757199	SCV000885340	uncertain significance	not provided	2018-03-25	criteria provided, single submitter	clinical testing	The DYNC2H1 c.6551A>T; p.Asp2184Val variant (rs201967064, ClinVar variant ID 281769) was found in the compound heterozygous state along with another DYNC2H1 variant (p.Tyr2016Cys) in two miscarriages from a family with recurrant pregnancy loss (Qiao 2106). This variant is listed in the genome Aggregation Database (gnomAD) with an African population frequency of 0.3% (identified on 75 out of 23,960 chromosomes). The aspartic acid at position 2184 is moderately conserved, considering 28 species, and computational analyses of the effects of the p.Asp2184Val variant on protein structure and function do not predict a deleterious effect (SIFT: tolerated, PolyPhen-2: benign). Based on the available information, the clinical significance of the p.Asp2184Val variant cannot be determined with certainty.
Genetic Services Laboratory, University of Chicago	RCV000365728	SCV002070178	uncertain significance	not specified	2020-03-17	criteria provided, single submitter	clinical testing	The sequence change, c.6551A>T, in exon 41 that results in an amino acid change, p.Asp2184Val. This sequence change has been previously reported in product of conception samples of a couple with recurrent miscarriages in the compound heterozygous state along with other missense change, p.Tyr2016Cys, in the same gene (PMID: 26826164). No functional studies were performed. This sequence change has been described in the gnomAD database with a low population frequency of 0.32% in the African subpopulation (dbSNP rs201967064). The p.Asp2184Val change affects a moderately conserved amino acid residue located in a domain of the DYNC2H1 protein that is known to be functional. The p.Asp2184Val substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Asp2184Val change remains unknown at this time.
GeneDx	RCV000757199	SCV002512925	uncertain significance	not provided	2022-04-26	criteria provided, single submitter	clinical testing	Identified in the the heterozygous state in an indvidual whose partner had recurrent miscarriage and was heterozygous for another variant in the DYNC2H1 gene (Qiao et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26826164)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000365728	SCV004813763	likely benign	not specified	2024-02-20	criteria provided, single submitter	clinical testing	Variant summary: DYNC2H1 c.6551A>T (p.Asp2184Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a neutral effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 248402 control chromosomes, predominantly at a frequency of 0.0028 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is slightly higher than the estimated maximal expected allele frequency for a pathogenic variant in DYNC2H1 causing Short-rib thoracic dysplasia phenotype (0.0025), suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.6551A>T has been reported in the literature in one individual affected with recurrent early pregnancy loss. These report(s) do not provide unequivocal conclusions about association of the variant with Short-rib thoracic dysplasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26826164). ClinVar contains an entry for this variant (Variation ID: 281769). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003939950	SCV004762623	likely benign	DYNC2H1-related disorder	2023-10-12	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).