Submissions for variant NM_001384474.1(LOXHD1):c.1570C>T (p.Arg524Cys)

gnomAD frequency: 0.00295  dbSNP: rs192376005

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150987	SCV000198674	benign	not specified	2017-05-18	criteria provided, single submitter	clinical testing	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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000150987	SCV000297374	uncertain significance	not specified	2015-10-30	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000444913	SCV000511316	uncertain significance	not provided	2017-01-25	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
Counsyl	RCV000477928	SCV000790138	uncertain significance	Autosomal recessive nonsyndromic hearing loss 77	2017-03-06	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000150987	SCV000858613	likely benign	not specified	2017-12-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000444913	SCV000977409	likely benign	not provided	2018-06-12	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000444913	SCV001023608	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000477928	SCV001283371	uncertain significance	Autosomal recessive nonsyndromic hearing loss 77	2017-04-27	criteria provided, single submitter	clinical testing	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.
Athena Diagnostics	RCV000444913	SCV001476663	likely benign	not provided	2020-07-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000150987	SCV002104085	benign	not specified	2022-02-23	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000444913	SCV004810854	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	LOXHD1: BS2
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477928	SCV000536796	uncertain significance	Autosomal recessive nonsyndromic hearing loss 77	2015-09-30	no assertion criteria provided	research
Natera, Inc.	RCV000477928	SCV001463934	likely benign	Autosomal recessive nonsyndromic hearing loss 77	2020-01-08	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003917474	SCV004732464	likely benign	LOXHD1-related disorder	2019-07-31	no assertion criteria provided	clinical testing	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).