rs192376005

chr18-46592017-G-Achr18-46592017-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001384474.1(LOXHD1):c.1570C>T(p.Arg524Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00305 in 1,552,186 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 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. R524H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (5 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:9
• Conservation: PhyloP100: 9.27

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.024916917).
• BP6: Variant 18-46592017-G-A is Benign according to our data. Variant chr18-46592017-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 163930.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=6, Uncertain_significance=4}. Variant chr18-46592017-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00282 (430/152276) while in subpopulation AMR AF= 0.00883 (135/15296). AF 95% confidence interval is 0.00761. There are 1 homozygotes in gnomad4. There are 214 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXHD1	NM_001384474.1	c.1570C>T	p.Arg524Cys	missense_variant	12/41	ENST00000642948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXHD1	ENST00000642948.1	c.1570C>T	p.Arg524Cys	missense_variant	12/41		NM_001384474.1	P1
LOXHD1	ENST00000536736.5	c.1570C>T	p.Arg524Cys	missense_variant	12/40	5
LOXHD1	ENST00000441551.6	c.1570C>T	p.Arg524Cys	missense_variant	12/39	5
LOXHD1	ENST00000335730.6	n.883C>T		non_coding_transcript_exon_variant	5/27	2

Frequencies

GnomAD3 genomes AF: 0.00283 AC: 431 AN: 152158 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00890

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00370

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00274 AC: 440 AN: 160600 Hom.: 1 AF XY: 0.00254 AC XY: 214 AN XY: 84096

Gnomad AFR exome AF: 0.000769

Gnomad AMR exome AF: 0.00435

Gnomad ASJ exome AF: 0.00538

Gnomad EAS exome AF: 0.0000883

Gnomad SAS exome AF: 0.000263

Gnomad FIN exome AF: 0.000409

Gnomad NFE exome AF: 0.00398

Gnomad OTH exome AF: 0.00371

GnomAD4 exome AF: 0.00308 AC: 4306 AN: 1399910 Hom.: 5 Cov.: 32 AF XY: 0.00291 AC XY: 2012 AN XY: 690436

Gnomad4 AFR exome AF: 0.000601

Gnomad4 AMR exome AF: 0.00420

Gnomad4 ASJ exome AF: 0.00401

Gnomad4 EAS exome AF: 0.0000560

Gnomad4 SAS exome AF: 0.000341

Gnomad4 FIN exome AF: 0.000323

Gnomad4 NFE exome AF: 0.00354

Gnomad4 OTH exome AF: 0.00284

GnomAD4 genome AF: 0.00282 AC: 430 AN: 152276 Hom.: 1 Cov.: 32 AF XY: 0.00287 AC XY: 214 AN XY: 74448

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.00883

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00370

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00346 Hom.: 3

Bravo AF: 0.00312

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000723 AC: 1

ESP6500EA AF: 0.00314 AC: 10

ExAC AF: 0.00168 AC: 45

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 24, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	LOXHD1: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 25, 2017	- -

Autosomal recessive nonsyndromic hearing loss 77 Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 06, 2017	- -
Uncertain significance, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Sep 30, 2015	- -
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. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 08, 2020	- -

not specified Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 18, 2017	p.Arg524Cys in exon 12 of LOXHD1: This variant is not expected to have clinical significance because it has been identified in 0.5% (44/8578) of Ashkenazi Jewis h chromosomes and 0.4% (291/73944) of European chromosomes including 1 homozygot e by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs192376005}. This variant has also been reported in seven members of one fam ily with autosomal dominant, late onset Fuchs corneal dystrophy (FCD); however, one affected family member did not carry this variant and functional studies wer e not strongly supportive of pathogenicity (Riazzudin 2012). In summary, this va riant is benign based on its frequency in the general population and the evidenc e against an association with FCD, primarily the non-segregation. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 26, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 30, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 23, 2022	Variant summary: LOXHD1 c.1570C>T (p.Arg524Cys) 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 0.0027 in 160600 control chromosomes including one homozygote (gnomAD), predominantly at a frequency of 0.0044 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in LOXHD1 causing Nonsyndromic Hearing Loss And Deafness, Type 77 phenotype (0.0011), suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.1570C>T has been reported in the literature in individuals affected with Nonsyndromic Hearing Loss And Deafness, Type 77 (Sheppard_2018), however this report does 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. Eleven ClinVar submitters have assessed the variant since 2014: five have classified the variant as of uncertain significance, five as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as benign. -

LOXHD1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 31, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.0054	T
BayesDel_noAF	Pathogenic	0.22
Cadd	Pathogenic	28
Dann	Uncertain	0.99
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.025	T;T;T
MetaSVM	Uncertain	-0.021	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.5	D;.;.
REVEL	Pathogenic	0.66
Sift	Benign	0.17	T;.;.
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		1.0	D;.;.
Vest4		0.78
MVP		0.72
ClinPred		0.026	T
GERP RS		6.1
Varity_R		0.43
gMVP		0.75

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: rs192376005; hg19: chr18-44171980; COSMIC: COSV59663574;