Submissions for variant NM_144666.3(DNHD1):c.11207-9_11207del

dbSNP: rs759052984

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002605872	SCV003492251	likely pathogenic	not provided	2022-06-28	criteria provided, single submitter	clinical testing	This variant results in the deletion of part of exon 35 of the DNHD1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DNHD1 are known to be pathogenic (PMID: 34932939). This variant is present in population databases (rs759052984, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with DNHD1-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017961	SCV004847407	likely pathogenic	Male infertility with spermatogenesis disorder	2024-01-08	criteria provided, single submitter	clinical testing	The c.11207-9_11207delTACCCCAAGT variant in DNHD1 has not been previously reported in individuals with asthenoteratozoospermia but has been been reported by other clinical laboratories in ClinVar (Variation ID 2175958). It has also been identified in 0.17% (71/41440) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This variant is a deletion that spans the acceptor canonical splice site that involves exon 35, which is predicted to lead to altered splicing. Loss of function variants in DNHD1 gene have been reported in individuals with autosomal recessive asthenoteratozoospermia (Tan 2022 PMID: 34932939, Martinez 2023 PMID: 36768883). Additionally, knockout mouse models have shown that mice without DNHD1 had infertility with decreased sperm concentration and motility rate and abnormal sperm flagella, recapitulating the human phenotype (Tan 2022 PMID: 34932939). Additionally, DNHD1 was absent in the flagella of individuals with asthenoteratozoospermia (Tan 2022 PMID: 34932939, Martinez 2023 PMID: 36768883). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive asthenoteratozoospermia. ACMG/AMP Criteria applied: PVS1, PM2_Supporting.
PreventionGenetics, part of Exact Sciences	RCV003953906	SCV004774761	uncertain significance	DNHD1-related disorder	2025-02-12	no assertion criteria provided	clinical testing	To our knowledge, this variant has not been reported in any affected individuals in the literature. This variant is reported in 0.13% of alleles in individuals of African descent in gnomAD. Early termination changes up and downstream of this variant have been reported in affected individuals. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.