chr18-46566443-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001384474.1(LOXHD1):c.2251C>T(p.Arg751Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000818 in 1,549,294 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R751R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00056 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00085 ( 1 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 4.68

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 77
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Fuchs' endothelial dystrophy
Inheritance: AD Classification: LIMITED Submitted by: Illumina

LOXHD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.090696424).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1 link	c.2251C>T	p.Arg751Trp	missense_variant	Exon 17 of 41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LOXHD1	ENST00000642948.1 link	c.2251C>T	p.Arg751Trp	missense_variant	Exon 17 of 41		NM_001384474.1	ENSP00000496347.1	A0A2R8Y7K4
LOXHD1	ENST00000536736.5 link	c.2251C>T	p.Arg751Trp	missense_variant	Exon 17 of 40	5		ENSP00000444586.1	F5GZB4
LOXHD1	ENST00000441551.6 link	c.2251C>T	p.Arg751Trp	missense_variant	Exon 17 of 39	5		ENSP00000387621.2	Q8IVV2-1
LOXHD1	ENST00000335730.6 link	n.1564C>T		non_coding_transcript_exon_variant	Exon 10 of 27	2

Frequencies

GnomAD3 genomes

AF:

0.000559

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000853

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000538

AC:

AN:

156082

AF XY:

0.000582

show subpopulations

Gnomad AFR exome

AF:

0.000231

Gnomad AMR exome

AF:

0.000445

Gnomad ASJ exome

AF:

0.00130

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000672

Gnomad NFE exome

AF:

0.000888

Gnomad OTH exome

AF:

0.000900

GnomAD4 exome

AF:

0.000847

AC:

1183

AN:

1397004

Hom.:

Cov.:

AF XY:

0.000808

AC XY:

557

AN XY:

689058

show subpopulations

African (AFR)

AF:

0.000127

AC:

AN:

31596

American (AMR)

AF:

0.000420

AC:

AN:

35702

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

25182

East Asian (EAS)

AF:

0.000112

AC:

AN:

35732

South Asian (SAS)

AF:

0.0000379

AC:

AN:

79226

European-Finnish (FIN)

AF:

0.0000638

AC:

AN:

47022

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00100

AC:

1083

AN:

1078866

Other (OTH)

AF:

0.000707

AC:

AN:

57980

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

116

175

233

291

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000558

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41560

American (AMR)

AF:

0.000523

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000853

AC:

AN:

68016

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000491

Hom.:

Bravo

AF:

0.000589

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00145

AC:

ESP6500EA

AF:

0.00251

AC:

ExAC

AF:

0.000803

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77

Uncertain:4

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

May 11, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 15, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided

Uncertain:3

Feb 08, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 751 of the LOXHD1 protein (p.Arg751Trp). This variant is present in population databases (rs376539851, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of Fuchs corneal dystrophy (PMID: 22341973). ClinVar contains an entry for this variant (Variation ID: 47929). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects LOXHD1 function (PMID: 22341973). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:2

May 07, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg751Trp variant in LOXHD1 has been previously identified by our laboratory in four individuals with hearing loss; however a second variant in trans (on the other copy of the gene) was not identified in any of these individuals. This variant has been identified in 0.13% (12/8778) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs376539851). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. The p.Arg751Trp variant has been seen in the heterozygous state in one individual with late-onset Fuchs corneal dystrophy (FCD); however the hearing status was not reported (Riazuddin 2012). This variant's association with FCD has not been reported in other affected individuals, which, given the frequency in the general population and presumed autosomal dominant inheritance pattern of FCD, does not support a strong correlation between this variant and FCD. It has also been reported in an individual with eosinophilic esophagitis, but the LOXHD1 gene has not been associated with this condition. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg751Trp variant is uncertain. ACMG/AMP Criteria applied: None. -

Aug 16, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: LOXHD1 c.2251C>T (p.Arg751Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00054 in 156082 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LOXHD1 causing Nonsyndromic Hearing Loss And Deafness, Type 77 (0.00054 vs 0.0011), allowing no conclusion about variant significance. c.2251C>T has been reported in the literature in at least one individual affected with Fuchs corneal dystrophy, however no further clinical information was provided (e.g. Riazuddin_2012). This report does not provide unequivocal conclusions about association of the variant with Nonsyndromic Hearing Loss And Deafness, Type 77. At least one publication reports experimental evidence evaluating an impact on protein function and found the variant resulted in cytoplasmic aggregates when expressed in retinal pigment epithelium cells (Riazuddin_2012); however, the clinical significance of this finding is currently unclear and does not allow convincing conclusions about the variant effect. The following publication has been ascertained in the context of this evaluation (PMID: 22341973). ClinVar contains an entry for this variant (Variation ID: 47929). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Benign

-0.036

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Benign

0.064

MetaRNN

Benign

0.091

T;T;T

MetaSVM

Uncertain

-0.18

PhyloP100

4.7

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-5.5

D;.;.

REVEL

Uncertain

0.57

Sift

Uncertain

0.0030

D;.;.

Sift4G

Pathogenic

0.0010

D;.;D

Polyphen

1.0

D;.;.

Vest4

0.79

MVP

0.41

ClinPred

0.22

GERP RS

3.9

Varity_R

0.27

gMVP

0.81

Mutation Taster

=58/42

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over