rs201587138

Positions:

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.Arg1494*) 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 (★★). 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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20O:1

Conservation

PhyloP100: 2.00

Variant links:

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]

LOXHD1 links:

LOXHD1 (HGNC:):

LOXHD1 links:

Genome browser will be placed here

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

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	Protein	UniProt
LOXHD1	NM_001384474.1 linkuse as main transcript	c.4480C>T	p.Arg1494*	stop_gained	29/41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1 linkuse as main transcript	c.4480C>T	p.Arg1494*	stop_gained	29/41		NM_001384474.1	ENSP00000496347.1		A0A2R8Y7K4

Frequencies

GnomAD3 genomes

AF:

0.000625

AC:

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.000661

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00112

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000611

AC:

AN:

158746

Hom.:

AF XY:

0.000550

AC XY:

AN XY:

83594

show subpopulations

Gnomad AFR exome

AF:

0.000114

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.000822

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000176

Gnomad FIN exome

AF:

0.000709

Gnomad NFE exome

AF:

0.00108

Gnomad OTH exome

AF:

0.000446

GnomAD4 exome

AF:

0.00108

AC:

1514

AN:

1399408

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

720

AN XY:

690212

show subpopulations

Gnomad4 AFR exome

AF:

0.000158

Gnomad4 AMR exome

AF:

0.000252

Gnomad4 ASJ exome

AF:

0.000437

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.000751

Gnomad4 NFE exome

AF:

0.00130

Gnomad4 OTH exome

AF:

0.000603

GnomAD4 genome

AF:

0.000624

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.000511

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.000661

Gnomad4 NFE

AF:

0.00112

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000991

Hom.:

Bravo

AF:

0.000593

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000723

AC:

ESP6500EA

AF:

0.00157

AC:

ExAC

AF:

0.000483

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77

Pathogenic:9Other:1

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	Fulgent Genetics, Fulgent Genetics	Mar 22, 2022	- -
Likely pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Oct 26, 2015	- -
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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 15, 2024	Criteria applied: PVS1,PM3_STR -
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	Revvity Omics, Revvity	Apr 15, 2021	- -
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. -

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2019	- -

Nonsyndromic genetic hearing loss

Pathogenic:2

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. -
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. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2024

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; García-García, 2020). Based on the available evidence, this alteration is classified as pathogenic. -

LOXHD1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 29, 2024

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. -

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

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.85

Vest4

0.48

GERP RS

4.2

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over