ClinVar Miner

Submissions for variant NM_144612.6(LOXHD1):c.4714C>T (rs75949023)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000023981 SCV000893496 pathogenic Deafness, autosomal recessive 77 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000627214 SCV000748201 likely pathogenic not provided 2018-03-08 criteria provided, single submitter clinical testing The R1572X variant in the LOXHD1 gene has been reported previously in two unrelated Ashkenazi Jewish families with autosomal recessive nonsyndromic hearing loss, however, affected individuals were not tested for other genes associated with nonsyndromic hearing loss (Edvardson et al., 2011). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R1572X variant is observed in 24/8214 (0.29%) alleles from individuals of Ashkenazi Jewish background in large population cohorts, and no individuals were reported to be homozygous (Lek et al., 2016). We interpret R1572X as a likely pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000023981 SCV000914816 likely pathogenic Deafness, autosomal recessive 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.
Invitae RCV000627214 SCV000954684 pathogenic not provided 2018-12-11 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. This variant is present in population databases (rs75949023, ExAC 0.07%). This variant has been observed to segregate with autosomal recessive hearing loss in several Ashkenazi Jewish families (PMID: 21465660). ClinVar contains an entry for this variant (Variation ID: 30990). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in LOXHD1 are known to be pathogenic (PMID: 19732867, 21465660, 25792669). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized 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.
OMIM RCV000023981 SCV000045272 pathogenic Deafness, autosomal recessive 77 2011-05-01 no assertion criteria provided literature only

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