Submissions for variant NM_001384474.1(LOXHD1):c.889A>C (p.Thr297Pro)

gnomAD frequency: 0.00056  dbSNP: rs117747744

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155153	SCV000204839	uncertain significance	not specified	2013-11-25	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Thr297Pro varia nt in LOXHD1 has not been reported in individuals with hearing loss, but has bee n identified in 1.2% (2/170) of European American and in 0.6% (1/178) of British chromosomes by the 1000 Genomes Project, as well as in 0.1% (4/3182) of Europea n American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.wash ington.edu/EVS/; dbSNP rs117747744). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic ro le. The threonine (Thr) residue at position 297 is not conserved through species , and computational analyses (biochemical amino acid properties, AlignGVGD, Poly Phen2, and SIFT) suggest that the Thr297Pro variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In s ummary, the clinical significance of this variant cannot be determined with cert ainty; however, based upon its presence in the general population and the comput ational data, we lean towards a more likely benign role.
Illumina Laboratory Services, Illumina	RCV000339301	SCV000408778	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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001723724	SCV002010020	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001723724	SCV003261735	uncertain significance	not provided	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 297 of the LOXHD1 protein (p.Thr297Pro). This variant is present in population databases (rs117747744, gnomAD 0.1%). 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: 178405). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Natera, Inc.	RCV000339301	SCV001454089	uncertain significance	Autosomal recessive nonsyndromic hearing loss 77	2020-09-16	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001723724	SCV001954381	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001723724	SCV001964316	uncertain significance	not provided		no assertion criteria provided	clinical testing