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rs188119157

chr18-46563166-G-Achr18-46563166-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_001384474.1(LOXHD1):c.2497C>T(p.Arg833Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000451 in 1,530,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

LOXHD1
NM_001384474.1 stop_gained

Scores

2
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 4.37
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1
?
    PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 18-46563166-G-A is Pathogenic according to our data. Variant chr18-46563166-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47930.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Likely_pathogenic=3, Uncertain_significance=1}. Variant chr18-46563166-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LOXHD1NM_001384474.1 linkuse as main transcriptc.2497C>T p.Arg833Ter stop_gained 18/41 ENST00000642948.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LOXHD1ENST00000642948.1 linkuse as main transcriptc.2497C>T p.Arg833Ter stop_gained 18/41 NM_001384474.1 P1
LOXHD1ENST00000536736.5 linkuse as main transcriptc.2497C>T p.Arg833Ter stop_gained 18/405
LOXHD1ENST00000441551.6 linkuse as main transcriptc.2497C>T p.Arg833Ter stop_gained 18/395 Q8IVV2-1
LOXHD1ENST00000335730.6 linkuse as main transcriptn.1810C>T non_coding_transcript_exon_variant 11/272

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000329
AC:
5
AN:
152000
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000656
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000253
AC:
4
AN:
158158
Hom.:
0
AF XY:
0.0000240
AC XY:
2
AN XY:
83332
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000885
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000492
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000464
AC:
64
AN:
1378914
Hom.:
0
Cov.:
30
AF XY:
0.0000459
AC XY:
31
AN XY:
675770
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000284
Gnomad4 SAS exome
AF:
0.0000127
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000556
Gnomad4 OTH exome
AF:
0.0000527
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000329
AC:
5
AN:
152000
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74244
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000656
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000967
Hom.:
0
Bravo
AF:
0.0000567
ExAC
?
    Exome Aggregation Consortium database
AF:
0.0000388
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:5Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 04, 2024This sequence change creates a premature translational stop signal (p.Arg833*) 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 (rs188119157, gnomAD 0.01%). 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: 47930). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMar 31, 2017- -
Autosomal recessive nonsyndromic hearing loss 77 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaAug 11, 2017The LOXHD1 c.2497C>T (p.Arg833Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The variant is reported at a frequency of 0.00002 in the East Asian population of the Genome Aggregation Database. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitterclinical testingDASANov 03, 2022The c.2497C>T;p.(Arg833*) variant creates a premature translational stop signal in the LOXHD1 gene. It is expected to result in an absent or disrupted protein product - PVS1. ClinVar contains an entry for this variant (ClinVar ID: 47930) - PS4_supporting. The variant is present at low allele frequencies population databases (rs188119157 – gnomAD 0.0002529%; ABraOM no frequency - https://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic. -
Hearing impairment Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingDepartment of Otolaryngology – Head & Neck Surgery, Cochlear Implant CenterApr 12, 2021PVS1_Strong, PM2_Moderate -
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMay 30, 2019The p.Arg833X variant in LOXHD1 been identified in 1 individual with sensorineural hearing loss; however, a second pathogenic variant in this gene was not identified (LMM data). It has also been identified in 0.05% (3/60924) of European chromosomes by gnomAD (https://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 833, which is predicted to lead to a truncated or absent protein. Loss of function of the LOXHD1 gene is strongly associated wish autosomal recessive 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 nonsyndromic hearing loss. ACMG/AMP Criteria applied: PVS1, PM2. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.19
Cadd
Pathogenic
41
Dann
Uncertain
1.0
Eigen
Benign
0.012
Eigen_PC
Benign
0.039
FATHMM_MKL
Uncertain
0.87
D
MutationTaster
Benign
1.0
A;A;A
Vest4
0.26
ClinPred
0.90
D
GERP RS
3.2

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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.

Other links and lift over

dbSNP: rs188119157; hg19: chr18-44143129; API