rs201587138
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001384474.1(LOXHD1):c.4480C>T(p.Arg1494Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,551,550 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R1494R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00062 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0011 ( 1 hom. )
Consequence
LOXHD1
NM_001384474.1 stop_gained
NM_001384474.1 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 2.00
Genes affected
LOXHD1 (HGNC:26521): (lipoxygenase homology PLAT domains 1) This gene encodes a highly conserved protein consisting entirely of PLAT (polycystin/lipoxygenase/alpha-toxin) domains, thought to be involved in targeting proteins to the plasma membrane. Studies in mice show that this gene is expressed in the mechanosensory hair cells in the inner ear, and mutations in this gene lead to auditory defects, indicating that this gene is essential for normal hair cell function. Screening of human families segregating deafness identified a mutation in this gene which causes DFNB77, a progressive form of autosomal-recessive nonsyndromic hearing loss (ARNSHL). Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Mar 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
?
Variant 18-46529227-G-A is Pathogenic according to our data. Variant chr18-46529227-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 178396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-46529227-G-A is described in Lovd as [Pathogenic]. Variant chr18-46529227-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| LOXHD1 | NM_001384474.1 | c.4480C>T | p.Arg1494Ter | stop_gained | 29/41 | ENST00000642948.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| LOXHD1 | ENST00000642948.1 | c.4480C>T | p.Arg1494Ter | stop_gained | 29/41 | NM_001384474.1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000625 AC: 95AN: 152026Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000611 AC: 97AN: 158746Hom.: 1 AF XY: 0.000550 AC XY: 46AN XY: 83594
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GnomAD4 exome AF: 0.00108 AC: 1514AN: 1399408Hom.: 1 Cov.: 32 AF XY: 0.00104 AC XY: 720AN XY: 690212
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:17Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 77 Pathogenic:8Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 22, 2022 | - - |
| not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Jan 01, 2019 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 19, 2020 | 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 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Mar 01, 2023 | 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. - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 15, 2021 | - - |
| Likely pathogenic, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Oct 26, 2015 | - - |
not provided Pathogenic:6
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | 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. ClinVar contains an entry for this variant (Variation ID: 178396). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 12, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 15, 2022 | 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) - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2019 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Nonsyndromic genetic hearing loss Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | INGEBI, INGEBI / CONICET | Jul 15, 2021 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 26, 2023 | 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. - |
Rare genetic deafness Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 08, 2018 | 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. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A;A;A;A
Vest4
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at