rs745683775

chr18-46560448-C-Gchr18-46560448-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001384474.1(LOXHD1):c.2696G>C(p.Arg899Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000465 in 1,543,534 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R899Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (0 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:4
• Conservation: PhyloP100: 2.74

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-46560448-C-G is Pathogenic according to our data. Variant chr18-46560448-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228819.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=3, Pathogenic=1}. Variant chr18-46560448-C-G is described in Lovd as [Likely_pathogenic]. Variant chr18-46560448-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXHD1	NM_001384474.1	c.2696G>C	p.Arg899Pro	missense_variant	19/41	ENST00000642948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXHD1	ENST00000642948.1	c.2696G>C	p.Arg899Pro	missense_variant	19/41		NM_001384474.1	P1
LOXHD1	ENST00000536736.5	c.2696G>C	p.Arg899Pro	missense_variant	19/40	5
LOXHD1	ENST00000441551.6	c.2598+2617G>C		intron_variant		5
LOXHD1	ENST00000335730.6	n.2009G>C		non_coding_transcript_exon_variant	12/27	2

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

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: 0.000514

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000179 AC: 27 AN: 150590 Hom.: 0 AF XY: 0.000225 AC XY: 18 AN XY: 80000

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000404

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: 0.000415

Gnomad OTH exome AF: 0.000229

GnomAD4 exome AF: 0.000488 AC: 679 AN: 1391348 Hom.: 0 Cov.: 37 AF XY: 0.000460 AC XY: 316 AN XY: 686620

Gnomad4 AFR exome AF: 0.0000633

Gnomad4 AMR exome AF: 0.0000280

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000485

Gnomad4 NFE exome AF: 0.000613

Gnomad4 OTH exome AF: 0.000224

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74348

Gnomad4 AFR AF: 0.0000965

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: 0.000514

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000204 Hom.: 0

Bravo AF: 0.000264

ExAC AF: 0.0000299 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 899 of the LOXHD1 protein (p.Arg899Pro). This variant is present in population databases (rs745683775, gnomAD 0.04%). This missense change has been observed in individual(s) with deafness (PMID: 26969326, 29676012, 32860223; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 228819). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 2023	Observed multiple times with another LOXHD1 variant in unrelated patients in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (Sloan-Heggen et al., 2016; Wesdorp et al., 2018; Shen et al., 2019); 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: 32149082, 29676012, 26969326, 30760222, 31547530, 31709873, 32860223, Morlet2021[Case Report], 33892339, 35875410) -

Autosomal recessive nonsyndromic hearing loss 77 Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 07, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Nonsyndromic genetic hearing loss Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jun 03, 2022

Variant summary: LOXHD1 c.2696G>C (p.Arg899Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 150590 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in LOXHD1 causing Nonsyndromic Hearing Loss And Deafness, Type 77 (0.00018 vs 0.0011), allowing no conclusion about variant significance. c.2696G>C has been reported in the literature in individuals affected with Nonsyndromic Hearing Loss And Deafness, Type 77 ( examples: Sloan-Heggen_2016, Wesdorp_2018, Brozkova_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014: VUS (n=4) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 15, 2016

The p.Arg899Pro variant in LOXHD1 has not been previously reported in individual s with hearing loss. Data from large population studies are insufficient to asse ss the frequency of this variant. Computational prediction tools and conservatio n analyses do not provide strong support for or against an impact to the protein . In summary, the clinical significance of the p.Arg899Pro variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Pathogenic	27
Dann	Uncertain	0.99
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.64	D;D
MetaSVM	Benign	-0.52	T
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.7	D;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.016	D;.
Sift4G	Uncertain	0.010	D;.
Polyphen		0.98	D;.
Vest4		0.90
MVP		0.37
ClinPred		0.45	T
GERP RS		4.1
gMVP		0.88

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: rs745683775; hg19: chr18-44140411;