Submissions for variant NM_001384474.1(LOXHD1):c.6182+1G>T

dbSNP: rs200375658

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001996115	SCV002280744	likely pathogenic	not provided	2023-09-08	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 38 of the LOXHD1 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 LOXHD1 are known to be pathogenic (PMID: 19732867, 21465660, 25792669). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LOXHD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1497507). 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.
King Laboratory, University of Washington	RCV003155457	SCV003844173	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 77	2023-02-28	criteria provided, single submitter	research	This variant occurred in compound heterozygosity with a LOXHD1 nonsense variant in a patient with bilateral sensorineural hearing loss of onset <18 years, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). The patient’s family has no other history of hearing loss. This variant is a single base pair substitution that is predicted to alter splicing. At the donor splice of LOXHD1 exon 21, the sequence change is GAA|gtagga > GAAttagga, NNSPLICE is 0.04 and 0.00, MaxEnt is 2.43 and -6.08 for reference and mutant sequences, respectively). A cryptic donor splice is predicted in the sequence of intron 21 with NNSPLICE 0.95 and MAxEnt 9.31. Consequences of altered splicing are (a) skipping of exon 21 resulting in a 133bp message deletion and premature stop at codon 1005 of 1115, or (b) activation of the cryptic donor splice resulting in a 42bp message insertion and inframe premature stop at codon 951. As of January 2023, this variant has been reported to ClinVar as likely pathogenic and is not found on gnomAD. Based on the prediction that this variant leads to a truncated protein, compound heterozygosity with a loss-of-function variant, and goodness of fit of genotype to phenotype, we conclude that this variant is likely pathogenic.