rs199847981

chr18-46560146-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001384474.1(LOXHD1):c.2998C>T(p.Arg1000Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000841 in 1,372,566 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R1000R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00069 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00086 (0 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 1.73

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0525434).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXHD1	NM_001384474.1	c.2998C>T	p.Arg1000Trp	missense_variant	19/41	ENST00000642948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXHD1	ENST00000642948.1	c.2998C>T	p.Arg1000Trp	missense_variant	19/41		NM_001384474.1	P1
LOXHD1	ENST00000536736.5	c.2998C>T	p.Arg1000Trp	missense_variant	19/40	5
LOXHD1	ENST00000441551.6	c.2599-2657C>T		intron_variant		5
LOXHD1	ENST00000335730.6	n.2311C>T		non_coding_transcript_exon_variant	12/27	2

Frequencies

GnomAD3 genomes AF: 0.000681 AC: 94 AN: 138096 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000811

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: 0.00131

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000530 AC: 84 AN: 158366 Hom.: 0 AF XY: 0.000431 AC XY: 36 AN XY: 83432

Gnomad AFR exome AF: 0.000230

Gnomad AMR exome AF: 0.0000404

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00125

Gnomad OTH exome AF: 0.000447

GnomAD4 exome AF: 0.000858 AC: 1059 AN: 1234382 Hom.: 0 Cov.: 38 AF XY: 0.000873 AC XY: 529 AN XY: 606190

Gnomad4 AFR exome AF: 0.000188

Gnomad4 AMR exome AF: 0.0000329

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000478

Gnomad4 SAS exome AF: 0.000270

Gnomad4 FIN exome AF: 0.000137

Gnomad4 NFE exome AF: 0.00103

Gnomad4 OTH exome AF: 0.000533

GnomAD4 genome AF: 0.000687 AC: 95 AN: 138184 Hom.: 0 Cov.: 31 AF XY: 0.000499 AC XY: 33 AN XY: 66160

Gnomad4 AFR AF: 0.000186

Gnomad4 AMR AF: 0.0000809

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00133

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000975 Hom.: 0

Bravo AF: 0.000544

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000723 AC: 1

ESP6500EA AF: 0.000629 AC: 2

ExAC AF: 0.000273 AC: 10

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, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 12, 2022	- -
Uncertain significance, flagged submission	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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 14, 2022	The LOXHD1 c.2998C>T (p.Arg1000Trp) missense variant results in the substitution of arginine at amino acid position 1000 with tryptophan. This variant has been reported in one study in which the variant was found in a compound heterozygous state with a second allele in LOXHD1 in an individual with hearing loss who also carried two alleles in TECTA, which is also associated with nonsyndromic hearing loss (PMID: 27068579). The c.2998C>T variant has been reported at a frequency of 0.001207 in the European (non-Finnish) population of the Genome Aggregation Database (version 2.1.1). Based on available evidence, the c.2998C>T (p.Arg1000Trp) variant is classified as a variant of uncertain significance for nonsyndromic genetic hearing loss. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 24, 2017	The R1000W variant in the LOXHD1 gene has been reported previously with another LOXHD1 variant in an individual with autosomal recessive nonsyndromic hearing loss (Sommen et al., 2016). However, it was unknown if the two variants were on the same LOXHD1 allele (in cis) or on opposite alleles (in trans), and this individual was also reported to have two variants that were thought to be causative in another hearing loss gene (Sommen et al., 2016). The R1000W variant is observed in 8/8,596 (0.09%) alleles from individuals of European (non-Finnish) background in the ExAC dataset (Lek et al., 2016). The R1000W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. While this substitution occurs at a position that is not conserved, in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R1000W as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Feb 23, 2022	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1000 of the LOXHD1 protein (p.Arg1000Trp). This variant is present in population databases (rs199847981, 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 nonsyndromic deafness (PMID: 27068579). ClinVar contains an entry for this variant (Variation ID: 449913). 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 19, 2019

Variant classified as Uncertain Significance - Favor Benign. The p.Arg1000Trp variant in LOXHD1 has been previously identified in 2 individuals with hearing loss (Sommen 2016, LMM data); however one of these individuals harbored two additional variants in the TECTA gene that were thought to be responsible for their hearing loss (Sommen 2016). This variant has also been identified in 0.1% (92/76204) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Arg1000Trp variant is uncertain, its frequency suggests it is more likely to be benign. ACMG/AMP Criteria applied: BS1_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.44
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.053	T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-4.1	D;.
REVEL	Benign	0.14
Sift	Uncertain	0.0050	D;.
Sift4G	Pathogenic	0.0010	D;.
Polyphen		1.0	D;.
Vest4		0.49
MVP		0.33
ClinPred		0.12	T
GERP RS		3.2
gMVP		0.56

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: rs199847981; hg19: chr18-44140109; COSMIC: COSV56062428; COSMIC: COSV56062428;