Submissions for variant NM_001384474.1(LOXHD1):c.1730T>G (p.Leu577Arg)

gnomAD frequency: 0.00017  dbSNP: rs727503147

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150985	SCV000198671	uncertain significance	not specified	2019-07-24	criteria provided, single submitter	clinical testing	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.
Eurofins Ntd Llc (ga)	RCV000727380	SCV000708017	uncertain significance	not provided	2017-05-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000669854	SCV000794646	uncertain significance	Autosomal recessive nonsyndromic hearing loss 77	2017-10-12	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000669854	SCV000915319	uncertain significance	Autosomal recessive nonsyndromic hearing loss 77	2017-08-10	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000727380	SCV001770273	uncertain significance	not provided	2024-04-09	criteria provided, single submitter	clinical testing	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 (PMID: 26969326); 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: 31547530, 23804846, 29676012, 31709873, 26969326, 28000701, 36515421)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000150985	SCV002599013	uncertain significance	not specified	2022-09-20	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000727380	SCV003257807	likely pathogenic	not provided	2024-08-12	criteria provided, single submitter	clinical testing	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 deafness (PMID: 23804846, 26969326, 28000701, 29676012, 31709873, 36515421). 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). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000727380	SCV004143065	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing	LOXHD1: PM2, PM3
Natera, Inc.	RCV000669854	SCV001454085	uncertain significance	Autosomal recessive nonsyndromic hearing loss 77	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003935268	SCV004755201	uncertain significance	LOXHD1-related disorder	2023-12-06	no assertion criteria provided	clinical testing	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.