ClinVar Miner

Submissions for variant NM_144612.6(LOXHD1):c.4480C>T (rs201587138)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Division of Human Genetics,Children's Hospital of Philadelphia RCV000381729 SCV000536821 likely pathogenic Deafness, autosomal recessive 77 2015-10-26 no assertion criteria provided research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000256002 SCV000345465 pathogenic not provided 2016-09-12 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000381729 SCV000893497 pathogenic Deafness, autosomal recessive 77 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000256002 SCV000322108 pathogenic not provided 2018-08-27 criteria provided, single submitter clinical testing The R1494X pathogenic variant in the LOXHD1 gene has been reported previously in association with autosomal recessive nonsyndromic hearing loss in an affected individual who was homozygous for the R1494X variant and in two affected siblings who were compound heterozygous for the R1494X variant and another nonsense variant (Diaz-Horta et al., 2012; Mori et al., 2015). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R1494X variant is observed in 88/73010 (0.12%) alleles from individuals of non-Finnish European background and in 123/182454 total alleles, including one homozygous individual, in large population cohorts (Lek et al., 2016). We interpret R1494X as a pathogenic variant.
GenomeConnect, ClinGen RCV000381729 SCV000986911 not provided Deafness, autosomal recessive 77 no assertion provided phenotyping only Variant interpretted as pathogenic and reported on 07/21/2017 by GTR ID Shodair Children's Hospital. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000381729 SCV000923732 pathogenic Deafness, autosomal recessive 77 2019-01-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000381729 SCV000408722 likely pathogenic Deafness, autosomal recessive 77 2017-04-27 criteria provided, single submitter clinical testing The LOXHD1 c.4480C>T (p.Arg1494Ter) variant is a stop-gained variant that has been reported in a total of three studies in which it is found in a homozygous state in two siblings and in a compound heterozygous state in three individuals (including two siblings), all with nonsyndromic hearing loss. The variant has also been reported in a heterozygous state in at least four unaffected individuals (Diaz-Horta et al. 2012; Eppsteiner et al. 2012; Mori et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00157 in the European American population of the Exome Sequencing Project. Due to the potential impact of stop-gained variants and supporting evidence, the p.Arg1494Ter variant is classified as likely pathogenic for recessively inherited nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000256002 SCV000964218 pathogenic not provided 2018-12-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1494*) in the LOXHD1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs201587138, ExAC 0.1%). This variant has been observed to segregate with non syndromic hearing loss in families (PMID: 23226338, 25792669) and has been reported in individuals with deafness (PMID: 22975204). ClinVar contains an entry for this variant (Variation ID: 178396). 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 RCV000155144 SCV000204830 pathogenic Rare genetic deafness 2018-08-08 criteria provided, single submitter clinical testing The p.Arg1494X variant in LOXHD1 has been reported in a homozygous state in two siblings with hearing loss from a consanguineous family (Diaz-Horta 2012) and in the compound heterozygous state with a second variant in LOXHD1 in two siblings in another family (Mori 2015). It has also been identified by our laboratory in three individuals with hearing loss, including one homozygote and two with a se cond LOXHD1 variant. This variant has been identified in 0.1% (88/73010) of Euro pean chromosomes by the Genome Aggregation Database (gnomAD, http://exac.broadin stitute.org; dbSNP rs201587138). This frequency is low enough to be consistent w ith autosomal recessive carrier frequency for hearing loss in the general popula tion. This nonsense variant leads to a premature termination codon at position 1 494, which is predicted to lead to a truncated or absent protein. Homozygous los s of function of the LOXHD1 gene is an established disease mechanism for hearing loss. In summary, this variant meets criteria to be classified as pathogenic in an autosomal recessive manner based upon the predicted impact of the variant, b iallelic states in multiple affected individuals, and segregation evidence. ACMG /AMP Criteria applied: PVS1; PM3_Strong.

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