Submissions for variant NM_001384474.1(LOXHD1):c.4480C>T (p.Arg1494Ter)

gnomAD frequency: 0.00069  dbSNP: rs201587138

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155144	SCV000204830	pathogenic	Rare genetic deafness	2018-08-08	criteria provided, single submitter	clinical testing	The p.Arg1494X variant in LOXHD1 has been reported in a homozygous state in two siblings with hearing loss from a consanguineous family (Diaz-Horta 2012) and in the compound heterozygous state with a second variant in LOXHD1 in two siblings in another family (Mori 2015). It has also been identified by our laboratory in three individuals with hearing loss, including one homozygote and two with a se cond LOXHD1 variant. This variant has been identified in 0.1% (88/73010) of Euro pean chromosomes by the Genome Aggregation Database (gnomAD, http://exac.broadin stitute.org; dbSNP rs201587138). This frequency is low enough to be consistent w ith autosomal recessive carrier frequency for hearing loss in the general popula tion. This nonsense variant leads to a premature termination codon at position 1 494, which is predicted to lead to a truncated or absent protein. Homozygous los s of function of the LOXHD1 gene is an established disease mechanism for hearing loss. In summary, this variant meets criteria to be classified as pathogenic in an autosomal recessive manner based upon the predicted impact of the variant, b iallelic states in multiple affected individuals, and segregation evidence. ACMG /AMP Criteria applied: PVS1; PM3_Strong.
GeneDx	RCV000256002	SCV000322108	pathogenic	not provided	2022-11-15	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22975204, 25792669, 26973026, 28984810, 31980526, 31589614, 33297549, 29676012, 26969326, 23226338, 29907799, 30622556, 34997062, 32860223)
Eurofins Ntd Llc (ga)	RCV000256002	SCV000345465	pathogenic	not provided	2016-09-12	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000381729	SCV000408722	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 77	2017-04-27	criteria provided, single submitter	clinical testing	The LOXHD1 c.4480C>T (p.Arg1494Ter) variant is a stop-gained variant that has been reported in a total of three studies in which it is found in a homozygous state in two siblings and in a compound heterozygous state in three individuals (including two siblings), all with nonsyndromic hearing loss. The variant has also been reported in a heterozygous state in at least four unaffected individuals (Diaz-Horta et al. 2012; Eppsteiner et al. 2012; Mori et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00157 in the European American population of the Exome Sequencing Project. Due to the potential impact of stop-gained variants and supporting evidence, the p.Arg1494Ter variant is classified as likely pathogenic for recessively inherited nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Fulgent Genetics, Fulgent Genetics	RCV000381729	SCV000893497	pathogenic	Autosomal recessive nonsyndromic hearing loss 77	2024-04-10	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000381729	SCV000923732	pathogenic	Autosomal recessive nonsyndromic hearing loss 77	2019-01-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000256002	SCV000964218	pathogenic	not provided	2025-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1494*) 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 (rs201587138, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individual(s) with deafness and non syndromic hearing loss (PMID: 22975204, 23226338, 25792669). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1147C>T (Arg383Term). ClinVar contains an entry for this variant (Variation ID: 178396). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000256002	SCV001245850	pathogenic	not provided	2019-04-01	criteria provided, single submitter	clinical testing
INGEBI, INGEBI / CONICET	RCV001544522	SCV001763595	pathogenic	Nonsyndromic genetic hearing loss	2021-07-15	criteria provided, single submitter	clinical testing	Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: The c.4480 C>T (p.Arg1494*) in LOXHD1 gene is predicted to cause a premature stop codon in biologically-relevant-exon 29/40 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism, NMD is predcited to occur, (PVS1). The variant filter allele frequency is 0.08% (from non-european alleles in gnomAD with 95%CI) applying to BS1_Supporting. The c.4480 C>T variant has been identified in trans with two different pathogenic/likley pathogenic in patients with diverse severity of hearing loss (PMID: 22975204 and PMID: 25792669). Besides, it was detected in homozygous state in two different probands (PMID: 23226338 and this study) meeting PM3_Strong. In addition to this, this variant segregated in two different family cases with two sibling with non-syndromic hearing loss, applying to PP1_Moderate (PMID: 23226338, 25792669). Taking all the information together together :PVS1, BS1_Supporting, PM3_Strong, PP1_Moderate, c.4480C>T is classified as Pathogenic for autosomal recessive non-syndromic hearing loss.
Revvity Omics, Revvity	RCV000381729	SCV002017172	pathogenic	Autosomal recessive nonsyndromic hearing loss 77	2021-04-15	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000381729	SCV002557229	pathogenic	Autosomal recessive nonsyndromic hearing loss 77	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 29 of 40). (P) 0252 - Variant is homozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (122 heterozygotes, 1 homozygote). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Other variants predicted to cause NMD have been reported in ClinVar as pathogenic in individuals with autosomal recessive deafness. (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported as pathogenic in patients with autosomal recessive deafness (ClinVar, PMID: 23226338, 25792669). (P) 1205 - Variant is maternally inherited. (N) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001544522	SCV004100192	pathogenic	Nonsyndromic genetic hearing loss	2023-09-26	criteria provided, single submitter	clinical testing	Variant summary: LOXHD1 c.4480C>T (p.Arg1494X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant allele was found at a frequency of 0.00061 in 158746 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in LOXHD1 causing Nonsyndromic Hearing Loss And Deafness, Type 77 (0.00061 vs 0.0011), allowing no conclusion about variant significance. c.4480C>T has been reported in the literature as a biallelic genotype in multiple individuals affected with Nonsyndromic Hearing Loss And Deafness, Type 77 and has been found to segregate with this phenotype in affected families (e.g. Diaz-Horta_2012, Maekawa_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23226338, 31547530). Thirteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000381729	SCV004175864	pathogenic	Autosomal recessive nonsyndromic hearing loss 77	2023-03-01	criteria provided, single submitter	clinical testing	The stop gain c.4480C>T (p.Arg1494Ter) variant in LOXHD1 gene has been reported in homozygous, compound heterozygous and heterozygous state in individuals affected with deafness and non syndromic hearing loss (Mori K, et. al., 2015). It has also been observed to segregate with disease in related individuals. The p.Arg1494Ter variant has allele frequency 0.07% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The nucleotide change c.4480C>T in LOXHD1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in LOXHD1 gene have been previously reported to be pathogenic (Mori K, et. al., 2015; Edvardson S, et. al., 2011). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV004639148	SCV005136603	pathogenic	Inborn genetic diseases	2024-06-06	criteria provided, single submitter	clinical testing	The c.4480C>T (p.R1494*) alteration, located in exon 29 (coding exon 29) of the LOXHD1 gene, consists of a C to T substitution at nucleotide position 4480. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 1494. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.065% (124/190118) total alleles studied. The highest observed frequency was 0.115% (88/76620) of European (non-Finnish) alleles. This variant has been identified in the homozygous state and in trans with another LOXHD1 variant in individuals with varying severities of sensorineural hearing loss (Diaz-Horta, 2012; Mori, 2015; Garc&iacute;a-Garc&iacute;a, 2020). Based on the available evidence, this alteration is classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000381729	SCV005368346	pathogenic	Autosomal recessive nonsyndromic hearing loss 77	2024-07-15	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM3_STR
Daryl Scott Lab, Baylor College of Medicine	RCV000381729	SCV005871341	pathogenic	Autosomal recessive nonsyndromic hearing loss 77	2024-01-01	criteria provided, single submitter	clinical testing	PVS1, PS4, PM3, PP1, BS1
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000381729	SCV000536821	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 77	2015-10-26	no assertion criteria provided	research
GenomeConnect, ClinGen	RCV000381729	SCV000986911	not provided	Autosomal recessive nonsyndromic hearing loss 77		no assertion provided	phenotyping only	Variant interpretted as pathogenic and reported on 07/21/2017 by GTR ID Shodair Children's Hospital. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Natera, Inc.	RCV000381729	SCV001460014	pathogenic	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+	RCV000256002	SCV001953942	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000256002	SCV001972574	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751298	SCV005366821	pathogenic	LOXHD1-related disorder	2024-07-29	no assertion criteria provided	clinical testing	The LOXHD1 c.4480C>T variant is predicted to result in premature protein termination (p.Arg1494*). This variant has been reported to be causative for autosomal recessive nonsyndromic hearing loss (Figure S1, Diaz-Horta et al. 2012. PubMed ID: 23226338; Mori et al 2015. PubMed ID: 25792669; Sheppard et al 2018. PubMed ID: 29907799; Morlet et al. 2021. PubMed ID: 35875410). This variant is reported in 0.11% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in LOXHD1 are expected to be pathogenic. This variant is interpreted as pathogenic.