Submissions for variant NM_001384474.1(LOXHD1):c.4376-6G>A

gnomAD frequency: 0.00006  dbSNP: rs369463541

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150969	SCV000198645	uncertain significance	not specified	2015-05-22	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The c.4376-6G>A var iant in LOXHD1 has been previously identified by our laboratory in 1 individual with hearing loss who carried a homozygous variant in another gene that was suff icient to explain their disease. It has also been identified in 1/8398 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs369463541). This variant is located in the 3' splice region. Comp utational tools do not suggest an impact to splicing. In addition, the guanine ( G) nucleotide at position c.4376-6 is not conserved in mammals or evolutionarily distant species and 9 mammals carry an adenine (A), supporting that a change at this position may be tolerated. However, this information is not predictive eno ugh to rule out pathogenicity. In summary, while the clinical significance of th e c.4376-6G>A variant is uncertain, the presence of the variant nucleotide in ot her species and predicted lack of impact on splicing suggest that it is more lik ely to be benign.
Illumina Laboratory Services, Illumina	RCV000367009	SCV000408724	uncertain significance	Autosomal recessive nonsyndromic hearing loss 77	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001395012	SCV001596710	likely benign	not provided	2024-10-08	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000367009	SCV001460015	uncertain significance	Autosomal recessive nonsyndromic hearing loss 77	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003945190	SCV004760099	likely benign	LOXHD1-related disorder	2019-03-18	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).