18-46566443-G-A

Position:

• chr18-46566443-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 4.68

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.090696424).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.2251C>T	p.Arg751Trp	missense_variant	17/41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.2251C>T	p.Arg751Trp	missense_variant	17/41		NM_001384474.1	ENSP00000496347	P1
LOXHD1	ENST00000536736.5	c.2251C>T	p.Arg751Trp	missense_variant	17/40	5		ENSP00000444586
LOXHD1	ENST00000441551.6	c.2251C>T	p.Arg751Trp	missense_variant	17/39	5		ENSP00000387621
LOXHD1	ENST00000335730.6	n.1564C>T		non_coding_transcript_exon_variant	10/27	2

Frequencies

GnomAD3 genomes AF: 0.000559 AC: 85 AN: 152172 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.000538 AC: 84 AN: 156082 Hom.: 0 AF XY: 0.000582 AC XY: 48 AN XY: 82426

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 SAS exome AF: 0.0000439

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.: 1 Cov.: 31 AF XY: 0.000808 AC XY: 557 AN XY: 689058

Gnomad4 AFR exome AF: 0.000127

Gnomad4 AMR exome AF: 0.000420

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.000112

Gnomad4 SAS exome AF: 0.0000379

Gnomad4 FIN exome AF: 0.0000638

Gnomad4 NFE exome AF: 0.00100

Gnomad4 OTH exome AF: 0.000707

GnomAD4 genome AF: 0.000558 AC: 85 AN: 152290 Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74466

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000853

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000416 Hom.: 0

Bravo AF: 0.000589

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00145 AC: 2

ESP6500EA AF: 0.00251 AC: 8

ExAC AF: 0.000803 AC: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77 Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 11, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 15, 2017	- -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 05, 2022	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. -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 08, 2017	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2020	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 16, 2024	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	T
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Uncertain	0.98
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.091	T;T;T
MetaSVM	Uncertain	-0.18	T
MutationTaster	Benign	0.95	D;D;D
PrimateAI	Uncertain	0.57	T
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	T
GERP RS		3.9
Varity_R		0.27
gMVP		0.81

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

Other links and lift over

dbSNP: rs376539851; hg19: chr18-44146406; COSMIC: COSV59661020;