ClinVar Miner

Submissions for variant NM_001347886.2(DNAH3):c.8833C>T (p.Arg2945Cys)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV004260386 SCV003880277 uncertain significance not specified 2023-02-16 criteria provided, single submitter clinical testing The c.8971C>T (p.R2991C) alteration is located in exon 53 (coding exon 53) of the DNAH3 gene. This alteration results from a C to T substitution at nucleotide position 8971, causing the arginine (R) at amino acid position 2991 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Institute of Reproductive and Stem Cell Engineering, Central South University RCV003388851 SCV004099292 likely pathogenic Spermatogenic failure 18 2023-10-26 criteria provided, single submitter research We identified two compound heterozygous variants c.6973T>C (p.Phe2325Leu) and c.8971C>T (p.Arg2991Cys) of DNAH3 in one fertile male patient diagnosed with asthenoteratozoospermia by using whole exome sequencing. The DNAH3 variant (Arg2991Cys) was shown to be highly conserved across multiple species and recorded as rare and predicted to be deleterious via in silico bioinformatics databases. Segregation analysis showed that the parents of this patient were heterozygous carriers. Three-dimensional modelling of the DNAH3 protein showed that this mutation disrupted hydrogen bonds and altered the distance between atoms of adjacent amino acids, which is likely to disrupt protein stability and function. Western blot have showed that expression of DNAH3 protein was decressed in the spermatozoa from the patient. In addition, the two Dnah3 knockout mice lines generated in our experiments recapitulated asthenoteratozoospermia similar to the patient. In summary, the variant (Arg2991Cys) meets our criteria to be classifiedas likely pathogenic based upon segregation studies, bioinformatics prediction in silico, and functional experiment evidence.

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