ClinVar Genomic variation as it relates to human health
NM_001384474.1(LOXHD1):c.2696G>C (p.Arg899Pro)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(1); Likely pathogenic(2); Uncertain significance(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001384474.1(LOXHD1):c.2696G>C (p.Arg899Pro)
Variation ID: 228819 Accession: VCV000228819.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q21.1 18: 46560448 (GRCh38) [ NCBI UCSC ] 18: 44140411 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 29, 2016 Feb 14, 2024 Jan 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001384474.1:c.2696G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001371403.1:p.Arg899Pro missense NM_144612.7:c.2696G>C NP_653213.6:p.Arg899Pro missense NC_000018.10:g.46560448C>G NC_000018.9:g.44140411C>G NG_016646.2:g.101586G>C - Protein change
- R899P
- Other names
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- Canonical SPDI
- NC_000018.10:46560447:C:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00025
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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LOXHD1 | - | - |
GRCh38 GRCh37 |
2463 | 2506 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (1) |
criteria provided, single submitter
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Jan 15, 2016 | RCV000219519.6 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 19, 2024 | RCV000485022.12 | |
Uncertain significance (2) |
criteria provided, single submitter
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Jan 12, 2018 | RCV001126895.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 3, 2022 | RCV002271468.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(May 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000708016.2
First in ClinVar: May 29, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(Jan 15, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000271939.2
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
The p.Arg899Pro variant in LOXHD1 has not been previously reported in individual s with hearing loss. Data from large population studies are insufficient to asse … (more)
The p.Arg899Pro variant in LOXHD1 has not been previously reported in individual s with hearing loss. Data from large population studies are insufficient to asse ss the frequency of this variant. Computational prediction tools and conservatio n analyses do not provide strong support for or against an impact to the protein . In summary, the clinical significance of the p.Arg899Pro variant is uncertain. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Sep 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000571182.4
First in ClinVar: Apr 27, 2017 Last updated: Sep 30, 2023 |
Comment:
Observed multiple times with another LOXHD1 variant in unrelated patients in published literature, but it is not known whether the variants occurred on the same … (more)
Observed multiple times with another LOXHD1 variant in unrelated patients in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (Sloan-Heggen et al., 2016; Wesdorp et al., 2018; Shen et al., 2019); 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: 32149082, 29676012, 26969326, 30760222, 31547530, 31709873, 32860223, Morlet2021[Case Report], 33892339, 35875410) (less)
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Uncertain significance
(Jan 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 77
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001286151.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Likely pathogenic
(Jun 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Nonsyndromic genetic hearing loss
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002555641.1
First in ClinVar: Aug 03, 2022 Last updated: Aug 03, 2022 |
Comment:
Variant summary: LOXHD1 c.2696G>C (p.Arg899Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more)
Variant summary: LOXHD1 c.2696G>C (p.Arg899Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 150590 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in LOXHD1 causing Nonsyndromic Hearing Loss And Deafness, Type 77 (0.00018 vs 0.0011), allowing no conclusion about variant significance. c.2696G>C has been reported in the literature in individuals affected with Nonsyndromic Hearing Loss And Deafness, Type 77 ( examples: Sloan-Heggen_2016, Wesdorp_2018, Brozkova_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014: VUS (n=4) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Jan 19, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002302741.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 899 of the LOXHD1 protein (p.Arg899Pro). … (more)
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 899 of the LOXHD1 protein (p.Arg899Pro). This variant is present in population databases (rs745683775, gnomAD 0.04%). This missense change has been observed in individual(s) with deafness (PMID: 26969326, 29676012, 32860223; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 228819). 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. For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Jan 07, 2020)
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no assertion criteria provided
Method: clinical testing
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Autosomal recessive deafness type 77
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001459813.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Recessive LOXHD1 variants cause a prelingual down-sloping hearing loss: genotype-phenotype correlation and three additional children with novel variants. | Yu S | International journal of pediatric otorhinolaryngology | 2021 | PMID: 33892339 |
Spectrum and frequencies of non GJB2 gene mutations in Czech patients with early non-syndromic hearing loss detected by gene panel NGS and whole-exome sequencing. | Safka Brozkova D | Clinical genetics | 2020 | PMID: 32860223 |
The etiological evaluation of sensorineural hearing loss in children. | van Beeck Calkoen EA | European journal of pediatrics | 2019 | PMID: 31152317 |
Further audiovestibular characterization of DFNB77, caused by deleterious variants in LOXHD1, and investigation into the involvement of Fuchs corneal dystrophy. | Wesdorp M | Clinical genetics | 2018 | PMID: 29676012 |
Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. | Sloan-Heggen CM | Human genetics | 2016 | PMID: 26969326 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LOXHD1 | - | - | - | - |
Text-mined citations for rs745683775 ...
HelpRecord last updated Feb 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.