Submissions for variant NM_001384474.1(LOXHD1):c.1537_1538del (p.Leu513fs)

dbSNP: rs1555683951

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000591723	SCV000703039	pathogenic	not provided	2016-11-14	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001449810	SCV001653103	likely pathogenic	Rare genetic deafness	2020-08-13	criteria provided, single submitter	clinical testing	The p.Leu513GlufsX17 variant in LOXHD1 has not been previously reported in individuals with hearing loss, but has been identified in 0.002% (1/62350) of European chromosomes by gnomAD. However, this frequency is low enough to be consistent with a recessive allele frequency. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 513 and leads to a premature termination codon 17 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the LOXHD1 gene is an established disease mechanism in autosomal recessive sensorineural hearing loss. 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 sensorineural hearing loss. ACMG/AMP Criteria applied: PVS1, PM2.
Revvity Omics, Revvity	RCV001783097	SCV002017173	pathogenic	Autosomal recessive nonsyndromic hearing loss 77	2020-08-05	criteria provided, single submitter	clinical testing
Invitae	RCV000591723	SCV002123871	pathogenic	not provided	2023-11-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu513Glufs*17) in the LOXHD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LOXHD1 are known to be pathogenic (PMID: 19732867, 21465660, 25792669). This variant is present in population databases (no rsID available, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with deafness (Invitae). ClinVar contains an entry for this variant (Variation ID: 498162). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000591723	SCV004143066	pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	LOXHD1: PVS1, PM2, PM3:Supporting
Natera, Inc.	RCV001783097	SCV002086333	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 77	2021-04-14	no assertion criteria provided	clinical testing