18-46592016-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001384474.1(LOXHD1):c.1571G>A(p.Arg524His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000336 in 1,552,202 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R524C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (1 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 7.32

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=0.21834913).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXHD1	NM_001384474.1	c.1571G>A	p.Arg524His	missense_variant	12/41	ENST00000642948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXHD1	ENST00000642948.1	c.1571G>A	p.Arg524His	missense_variant	12/41		NM_001384474.1	P1
LOXHD1	ENST00000536736.5	c.1571G>A	p.Arg524His	missense_variant	12/40	5
LOXHD1	ENST00000441551.6	c.1571G>A	p.Arg524His	missense_variant	12/39	5
LOXHD1	ENST00000335730.6	n.884G>A		non_coding_transcript_exon_variant	5/27	2

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000411 AC: 66 AN: 160600 Hom.: 1 AF XY: 0.000440 AC XY: 37 AN XY: 84104

Gnomad AFR exome AF: 0.000220

Gnomad AMR exome AF: 0.000685

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000878

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000417

Gnomad OTH exome AF: 0.000218

GnomAD4 exome AF: 0.000329 AC: 460 AN: 1399904 Hom.: 1 Cov.: 32 AF XY: 0.000378 AC XY: 261 AN XY: 690434

Gnomad4 AFR exome AF: 0.0000633

Gnomad4 AMR exome AF: 0.000700

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000560

Gnomad4 SAS exome AF: 0.000883

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000309

Gnomad4 OTH exome AF: 0.000327

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74478

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000347 Hom.: 0

Bravo AF: 0.000438

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000314 AC: 1

ExAC AF: 0.000447 AC: 12

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77 Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 17, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 23, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 28, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 524 of the LOXHD1 protein (p.Arg524His). This variant is present in population databases (rs187658135, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. 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: 47918). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 04, 2013

The Arg524His variant has not been reported in individuals affected with hearing loss, but has been identified in 1/3182 (0.03%) European American chromosomes b y the NHLBI Exome Sequencing Project and in 1/1000 (0.1%) chromosomes by the 100 0 Genome Project (http://evs.gs.washington.edu/EVS; dbSNP rs187658135). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide s trong support for or against an impact to the protein. This variant has also bee n identified in the heterozygous state in one individual with late onset Fuchs c orneal dystrophy (FCD), however hearing status was not reported (Riazuddin 2012) . This variant's association with FCD has not been reported in other affected in dividuals, which, taken together with the presumed autosomal dominant inheritanc e pattern of FCD, does not support a strong correlation between this variant and FCD. In summary, additional data is needed to determine the clinical significan ce of this variant. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2021

The c.1571G>A (p.R524H) alteration is located in exon 12 (coding exon 12) of the LOXHD1 gene. This alteration results from a G to A substitution at nucleotide position 1571, causing the arginine (R) at amino acid position 524 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Pathogenic	0.23
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Uncertain	0.20	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.8	D;.;.
REVEL	Uncertain	0.51
Sift	Benign	0.061	T;.;.
Sift4G	Pathogenic	0.0010	D;.;D
Polyphen		1.0	D;.;.
Vest4		0.65
MVP		0.41
ClinPred		0.34	T
GERP RS		6.1
Varity_R		0.31
gMVP		0.68

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: rs187658135; hg19: chr18-44171979;