rs727503147

chr18-46579709-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001384474.1(LOXHD1):c.1730T>G(p.Leu577Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000235 in 1,551,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:10
• Conservation: PhyloP100: 8.53

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXHD1	NM_001384474.1	c.1730T>G	p.Leu577Arg	missense_variant	13/41	ENST00000642948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXHD1	ENST00000642948.1	c.1730T>G	p.Leu577Arg	missense_variant	13/41		NM_001384474.1	P1
LOXHD1	ENST00000536736.5	c.1730T>G	p.Leu577Arg	missense_variant	13/40	5
LOXHD1	ENST00000441551.6	c.1730T>G	p.Leu577Arg	missense_variant	13/39	5
LOXHD1	ENST00000335730.6	n.1043T>G		non_coding_transcript_exon_variant	6/27	2

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000367

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000113 AC: 18 AN: 158826 Hom.: 0 AF XY: 0.0000957 AC XY: 8 AN XY: 83584

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000277

Gnomad OTH exome AF: 0.000223

GnomAD4 exome AF: 0.000240 AC: 336 AN: 1399472 Hom.: 0 Cov.: 31 AF XY: 0.000232 AC XY: 160 AN XY: 690240

Gnomad4 AFR exome AF: 0.0000949

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000298

Gnomad4 OTH exome AF: 0.000207

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152188 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74350

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000367

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000203 Hom.: 0

Bravo AF: 0.000170

ExAC AF: 0.0000361 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 27, 2021	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 577 of the LOXHD1 protein (p.Leu577Arg). This variant is present in population databases (rs727503147, gnomAD 0.03%). This missense change has been observed in individual(s) with autosomal recessive non-syndromic hearing loss (PMID: 23804846, 26969326, 28000701, 29676012, 31709873). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 163928). 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"). 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	GeneDx	Jul 20, 2022	Reported previously in an individual with autosomal recessive hearing loss, who was heterozygous for L577R and two other variants (E1957K and R1982X); however, familial segregation information was not included to determine phase of these variants (Sloan-Heggen et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26969326, 31547530, 28000701, 23804846, 29676012, 31709873) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	LOXHD1: PM2, PM3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 01, 2017	- -

Autosomal recessive nonsyndromic hearing loss 77 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 10, 2017	The LOXHD1 c.1730T>G (p.Leu577Arg) missense variant has been reported in at least three studies in which it is found in three individuals with congenital or childhood onset severe hearing loss, including in one in a compound heterozygous state with a frameshift variant, one in a compound heterozygous state with two additional LOXHD1 variants, the conformation of which was not determined, and one in a heterozygous state along with four additional variants of undetermined pathogenicity in four hearing loss-associated genes (Shearer et al. 2013; Sloan-Heggen et al. 2016; Zazo Seco et al. 2017). Control data are unavailable for the p.Leu577Arg variant, which is reported at a frequency of 0.00029 in the European (non-Finnish) population of Genome Aggregation Database. Based on the evidence, the p.Leu577Arg variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 12, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 24, 2019	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Leu577Arg variant in LOXHD1 has been previously reported in 5 individuals with hearing loss, including 1 who was confirmed to have a truncating LOXHD1 in trans, and 2 who were reported to have truncating LOXHD1 variants without phasing confirmed (Shearer 2013, Sloan-Heggen 2016, Wesdorp 2018, Zazo Seco 2017). This variant has also been identified in 0.02% (21/76696) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM3, PM2_Supporting, PP3. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 20, 2022	Variant summary: LOXHD1 c.1730T>G (p.Leu577Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 158826 control chromosomes (gnomAD). This frequency is not higher than predicted for a pathogenic variant in LOXHD1 causing Nonsyndromic Hearing Loss And Deafness, Type 77 (0.00011 vs 0.0011), allowing no conclusion about variant significance. c.1730T>G has been reported in the literature in individuals affected with Hearing Loss (examples: Shearer_2013, SloanHeggen_2016, Wesdrop_2018, and Zazo Seco_2017). However, in cases where two alleles were reported (including truncating variant as a second a allele) co-occurrences and/or co-segregation/phase were not specified. These reports do not provide unequivocal conclusions about association of the variant with Nonsyndromic Hearing Loss And Deafness, Type 77. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

LOXHD1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 06, 2023

The LOXHD1 c.1730T>G variant is predicted to result in the amino acid substitution p.Leu577Arg. This variant was reported in an individual with a hearing loss phenotype. However, two other variants in LOXHD1 were also detected in this individual (Patent 161, Table S3, Sloan-Heggen et al 2016. PubMed ID: 26969326). This variant has also been reported in the compound heterozygous state in other patients with hearing loss phenotypes (Table 1, Wesdorp et al. 2018. PubMed ID: 29676012; Table 1, Zazo Seco et al. 2017. PubMed ID: 28000701). This variant is reported in 0.027% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Pathogenic	26
Dann	Uncertain	0.98
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	0.63	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.5	D;.;.
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D;.;.
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		1.0	D;.;.
Vest4		0.93
MVP		0.58
ClinPred		0.77	D
GERP RS		5.2
Varity_R		0.41
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs727503147; hg19: chr18-44159672; COSMIC: COSV105903529;