Total submissions: 12
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Dasa | RCV000627214 | SCV007600081 | pathogenic | not provided | 2025-04-22 | criteria provided, single submitter | clinical testing | NM_001384474.1(LOXHD1):c.4714C>T (p.Arg1572*) introduces a premature termination codon predicted to result in loss of normal protein function. Loss-of-function is an established mechanism of disease for this gene. Segregation evidence has been reported in affected families. This variant has been recurrently observed in affected individuals with related phenotype in a genotype context consistent with recessive disease (PMID: 21465660; PMID: 25792669; PMID: 22341973). The variant is present at low frequency in population datasets. Based on the available data, this variant is classified as pathogenic. |
| Natera, |
RCV000023981 | SCV007535662 | pathogenic | Autosomal recessive nonsyndromic hearing loss 77 | 2025-09-29 | criteria provided, single submitter | clinical testing | The c.4714C>T variant in LOXHD1 is a nonsense variant predicted to introduce a stop codon at amino acid 1572. This variant is expected to result in nonsense mediated decay, truncation, or a dysfunctional protein product. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 33111345). Given the available evidence, this variant is classified as Pathogenic. |
| Genetics and Genomic Medicine Centre, |
RCV000023981 | SCV005873586 | pathogenic | Autosomal recessive nonsyndromic hearing loss 77 | 2021-12-11 | criteria provided, single submitter | clinical testing | |
| Dubai Health Genomic Medicine Center, |
RCV004798747 | SCV005420554 | pathogenic | Deafness | 2024-10-04 | criteria provided, single submitter | research | PVS1,PM3(strong),PM2 |
| Labcorp Genetics |
RCV000627214 | SCV000954684 | pathogenic | not provided | 2025-12-06 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg1572*) in the LOXHD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LOXHD1 are known to be pathogenic (PMID: 19732867, 21465660, 25792669). This variant is present in population databases (rs75949023, gnomAD 0.3%). This premature translational stop signal has been observed in individual(s) with autosomal recessive hearing loss (PMID: 21465660). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30990). For these reasons, this variant has been classified as Pathogenic. |
| Illumina Laboratory Services, |
RCV000023981 | SCV000914816 | likely pathogenic | Autosomal recessive nonsyndromic hearing loss 77 | 2018-10-22 | criteria provided, single submitter | clinical testing | The LOXHD1 c.4714C>T (p.Arg1572Ter) variant is a stop-gained variant that is predicted to cause a premature truncation of the protein. The p.Arg1572Ter variant has been reported in two studies in which it was found in a homozygous state in a total of nine probands from two unrelated, non-consanguineous Ashkenazi Jewish families and in a heterozygous state in an additional Ashkenazi Jewish proband in whom a second variant could not be identified (Edvardson et al. 2011; Tsai et al. 2013). In one of the families, the parents and three of the normal hearing siblings were found to be heterozygous for the variant, two unaffected siblings did not carry the variant, and five affected siblings were homozygous for the variant, suggesting that the variant segregated with disease in this family (Edvardson et al. 2011). In the second family, the four affected individuals were homozygous for the p.Arg1572Ter variant (Edvardson et al. 2011). The variant was reported in a heterozygous state in four out of 719 Ashkenazi Jewish controls and in one out of 44 healthy Ashkenazi Jewish centenarians (Edvardson et al. 2011; Freudenberg-Hua et al. 2014) and is reported at a frequency of 0.002922 in the Ashkenzi Jewish population of the Genome Aggregation Database. Due to the potential impact of stop-gained variants and the available evidence, the p.Arg1572Ter variant is classified as likely pathogenic for autosomal recessive non-syndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| Fulgent Genetics, |
RCV000023981 | SCV000893496 | pathogenic | Autosomal recessive nonsyndromic hearing loss 77 | 2024-05-16 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000627214 | SCV000748201 | pathogenic | not provided | 2024-04-05 | criteria provided, single submitter | clinical testing | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25792669, 25525159, 22341973, 26973026, 30096381, 29676012, 31547530, 25333069, 35875410, 31980526, 37240244, 30760222, 32149082, 35711932, 21465660) |
| Laboratory for Molecular Medicine, |
RCV000211793 | SCV000221196 | pathogenic | Rare genetic deafness | 2014-07-15 | criteria provided, single submitter | clinical testing | The p.Arg1572X variant in LOXHD1 has been reported in 2 homozygous Ashkenazi Jew ish individuals with nonsyndromic hearing loss, and it was found to segregate wi th disease in 7 homozygous affected family members (Edvardson 2011). This varia nt has been identified in 6/8670 European chromosomes by the Exome Aggregation C onsortium (ExAC, http://exac.broadinstitute.org; dbSNP rs75949023). Although th is variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 1572 which is predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic based upon segregation studies and the predicted imp act to the protein. |
| Prevention |
RCV004751222 | SCV005348314 | likely pathogenic | LOXHD1-related disorder | 2024-09-01 | no assertion criteria provided | clinical testing | The LOXHD1 c.4714C>T variant is predicted to result in premature protein termination (p.Arg1572*). This variant has been reported in the homozygous or compound heterozygous state in multiple individuals with autosomal recessive non-syndromic hearing loss and has been noted to segregate with the disorder in families (Edvardson et al. 2011. PubMed ID: 21465660; Wang et al. 2022. PubMed ID: 35711932). Nonsense variants in LOXHD1 are expected to be pathogenic. This variant is reported in 0.28% of alleles in individuals of Ashkenazi Jewish descent and 0.0066% of alleles in individuals of non-Finnish European descent in gnomAD; in at least one study, this variant was suggested to be a founder variant in the Ashkenazi Jewish population (Edvardson et al. 2011. PubMed ID: 21465660). This variant is interpreted as likely pathogenic. |
| Laboratory of Prof. |
RCV000023981 | SCV001164282 | pathogenic | Autosomal recessive nonsyndromic hearing loss 77 | 2018-05-07 | no assertion criteria provided | research | Recessive, congenital, severe-profound NSHL |
| OMIM | RCV000023981 | SCV000045272 | pathogenic | Autosomal recessive nonsyndromic hearing loss 77 | 2011-05-01 | no assertion criteria provided | literature only |