18-46524734-G-A

Position:

chr18-46524734-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001384474.1(LOXHD1):c.4714C>T(p.Arg1572*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000677 in 1,551,548 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 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000066 ( 1 hom. )

Consequence

LOXHD1
NM_001384474.1 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 2.14

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 18-46524734-G-A is Pathogenic according to our data. Variant chr18-46524734-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-46524734-G-A is described in Lovd as [Pathogenic]. Variant chr18-46524734-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.4714C>T	p.Arg1572*	stop_gained	30/41	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.4714C>T	p.Arg1572*	stop_gained	30/41		NM_001384474.1	ENSP00000496347.1		A0A2R8Y7K4

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000177

AC:

AN:

157920

Hom.:

AF XY:

0.000180

AC XY:

AN XY:

83168

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00283

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000660

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000657

AC:

AN:

1399392

Hom.:

Cov.:

AF XY:

0.0000609

AC XY:

AN XY:

690202

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00210

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000252

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000287

Gnomad4 OTH exome

AF:

0.000103

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000278

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.000236

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 22, 2018	The LOXHD1 c.4714C>T (p.Arg1572Ter) variant is a stop-gained variant that is predicted to cause a premature truncation of the protein. The p.Arg1572Ter variant has been reported in two studies in which it was found in a homozygous state in a total of nine probands from two unrelated, non-consanguineous Ashkenazi Jewish families and in a heterozygous state in an additional Ashkenazi Jewish proband in whom a second variant could not be identified (Edvardson et al. 2011; Tsai et al. 2013). In one of the families, the parents and three of the normal hearing siblings were found to be heterozygous for the variant, two unaffected siblings did not carry the variant, and five affected siblings were homozygous for the variant, suggesting that the variant segregated with disease in this family (Edvardson et al. 2011). In the second family, the four affected individuals were homozygous for the p.Arg1572Ter variant (Edvardson et al. 2011). The variant was reported in a heterozygous state in four out of 719 Ashkenazi Jewish controls and in one out of 44 healthy Ashkenazi Jewish centenarians (Edvardson et al. 2011; Freudenberg-Hua et al. 2014) and is reported at a frequency of 0.002922 in the Ashkenzi Jewish population of the Genome Aggregation Database. Due to the potential impact of stop-gained variants and the available evidence, the p.Arg1572Ter variant is classified as likely pathogenic for autosomal recessive non-syndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2011	- -
Pathogenic, no assertion criteria provided	research	Laboratory of Prof. Karen Avraham, Tel Aviv University	May 07, 2018	Recessive, congenital, severe-profound NSHL -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 15, 2021	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change creates a premature translational stop signal (p.Arg1572*) 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 (rs75949023, gnomAD 0.3%). This premature translational stop signal has been observed in individual(s) with autosomal recessive hearing loss (PMID: 21465660). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30990). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2024	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: 25792669, 25525159, 22341973, 26973026, 30096381, 29676012, 31547530, 25333069, 35875410, 31980526, 37240244, 30760222, 32149082, 35711932, 21465660) -

LOXHD1-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 01, 2024

The LOXHD1 c.4714C>T variant is predicted to result in premature protein termination (p.Arg1572*). This variant has been reported in the homozygous or compound heterozygous state in multiple individuals with autosomal recessive non-syndromic hearing loss and has been noted to segregate with the disorder in families (Edvardson et al. 2011. PubMed ID: 21465660; Wang et al. 2022. PubMed ID: 35711932). Nonsense variants in LOXHD1 are expected to be pathogenic. This variant is reported in 0.28% of alleles in individuals of Ashkenazi Jewish descent and 0.0066% of alleles in individuals of non-Finnish European descent in gnomAD; in at least one study, this variant was suggested to be a founder variant in the Ashkenazi Jewish population (Edvardson et al. 2011. PubMed ID: 21465660). This variant is interpreted as likely pathogenic. -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 15, 2014

The p.Arg1572X variant in LOXHD1 has been reported in 2 homozygous Ashkenazi Jew ish individuals with nonsyndromic hearing loss, and it was found to segregate wi th disease in 7 homozygous affected family members (Edvardson 2011). This varia nt has been identified in 6/8670 European chromosomes by the Exome Aggregation C onsortium (ExAC, http://exac.broadinstitute.org; dbSNP rs75949023). Although th is variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 1572 which is predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic based upon segregation studies and the predicted imp act to the protein. -

Deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Oct 04, 2024

PVS1,PM3(strong),PM2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.45

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.85

Vest4

0.40

GERP RS

0.59

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.

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