ClinVar Genomic variation as it relates to human health
NM_001146079.2(CLDN14):c.488C>T (p.Ala163Val)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001146079.2(CLDN14):c.488C>T (p.Ala163Val)
Variation ID: 228519 Accession: VCV000228519.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 21q22.13 21: 36461208 (GRCh38) [ NCBI UCSC ] 21: 37833506 (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 20, 2024 Jul 29, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001146079.2:c.488C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001139551.1:p.Ala163Val missense NM_001146077.2:c.488C>T NP_001139549.1:p.Ala163Val missense NM_001146078.3:c.488C>T NP_001139550.1:p.Ala163Val missense NM_012130.4:c.488C>T NP_036262.1:p.Ala163Val missense NM_144492.3:c.488C>T NP_652763.1:p.Ala163Val missense NC_000021.9:g.36461208G>A NC_000021.8:g.37833506G>A NG_011777.1:g.120362C>T - Protein change
- A163V
- Other names
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- Canonical SPDI
- NC_000021.9:36461207:G:A
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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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0.00040 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00026
The Genome Aggregation Database (gnomAD), exomes 0.00029
1000 Genomes Project 0.00040
The Genome Aggregation Database (gnomAD) 0.00046
1000 Genomes Project 30x 0.00047
Trans-Omics for Precision Medicine (TOPMed) 0.00043
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00046
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
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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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CLDN14 | - | - |
GRCh38 GRCh37 |
- | 221 | |
CLDN14-AS1 | - | - | - | GRCh38 | - | 188 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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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no classifications from unflagged records (1) |
no classifications from unflagged records
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Dec 7, 2023 | RCV000222605.5 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 21, 2022 | RCV000778641.6 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 29, 2023 | RCV001575532.11 |
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
Help
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
Help
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
Help
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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Likely pathogenic
(Sep 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 29
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000914968.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The CLDN14 c.488C>T (p.Ala163Val) missense variant was identified in a compound heterozygous state with a second missense variant in one individual with nonsyndromic hearing loss … (more)
The CLDN14 c.488C>T (p.Ala163Val) missense variant was identified in a compound heterozygous state with a second missense variant in one individual with nonsyndromic hearing loss (Sloan-Heggen et al. 2016). Pater et al (2017) reported the p.Ala163Val variant in a very large family from Newfoundland that was originally thought to be three separate families but detailed pedigree analysis revealed common ancestors. All ten individuals from this extended family with a rare audioprofile were found to be homozygous for the p.Ala163Val variant. A different audioprofile was identified in five additional individuals in the family with hearing loss. Of these five, one carried the p.Ala163Val variant in a heterozygous state; the remaining four did not carry this variant, and the authors suggest a second cause of hearing loss within the family. Seven additional unaffected members of this family were heterozygous for the p.Ala163Val variant. Analysis by Pater et al. (2017) of additional hearing loss families in Newfoundland revealed the variant in a homozygous state in two related individuals with the same audioprofile as the homozygotes from the extended family, and in a heterozygous state in two further unrelated individuals with hearing loss. The variant was also found in a heterozygous state in an unaffected relative of the two homozygotes. The p.Ala163Val variant was identified in a heterozygous state in four of 175 normal-hearing controls (Pater et al. 2017) and is reported at a frequency of 0.00070 in the European American population of the Exome Sequencing Project. Based on the evidence, the p.Ala163Val variant is classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Jun 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 29
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002556059.1
First in ClinVar: Aug 03, 2022 Last updated: Aug 03, 2022 |
Comment:
Variant summary: CLDN14 c.488C>T (p.Ala163Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: CLDN14 c.488C>T (p.Ala163Val) 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 0.00029 in 249754 control chromosomes (gnomAD), and is commonly reported in individuals of Newfoundland ancestry due to a founder effect (Pater_2017). c.488C>T has been reported in the literature in several individuals affected with Autosomal Recessive Nonsyndromic Hearing Loss, including one compound heterozygous individual (Sloan-Heggen_2016) and several homozygous individuals from 2 unrelated Newfoundland families (Pater_2017). All homozygous individuals had a unique audioprofile that distinguised them from heterozygous and non-carrier family members with unexplained hearing loss (Pater_2017). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submitters have assessed the variant since 2014: one classified the variant as VUS, two as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 29
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002769096.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness 29 (MIM#614035). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (89 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated fourth transmembrane domain (PMID: 27838790). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as a VUS, but has more recently and consistently been classified as likely pathogenic or pathogenic (ClinVar, deafnessvariationdatabase.org). It has been observed in a compound heterozygous individual with congenital-onset nonsyndromic hearing loss (NSHL), and is regarded as a Newfoundland founder variant, having been observed in many homozygous individuals with mid-high frequency NSHL (PMID: 27838790, PMID: 26969326). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been observed in a total of twelve homozygous individuals, all linked through haplotype mapping to be part of a single large family (PMID: 27838790). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Likely pathogenic
(Jul 27, 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: SCV001802547.5
First in ClinVar: Aug 21, 2021 Last updated: Aug 05, 2023 |
Comment:
Observed with a second CLDN14 variant in a patient with hearing loss in published literature (Sloan-Heggen et al., 2016); In silico analysis supports that this … (more)
Observed with a second CLDN14 variant in a patient with hearing loss in published literature (Sloan-Heggen et al., 2016); 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: 29447821, 23991001, 27838790, 26969326, 36147510, 36833326) (less)
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Pathogenic
(Jul 29, 2023)
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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: SCV002131454.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function … (more)
For these reasons, this variant has been classified as Pathogenic. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 228519). This missense change has been observed in individual(s) with autosomal recessive nonsyndromic deafness (PMID: 27838790). It is commonly reported in individuals of Newfoundland ancestry (PMID: 27838790). This variant is present in population databases (rs143797113, gnomAD 0.06%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 163 of the CLDN14 protein (p.Ala163Val). (less)
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Uncertain significance
(Oct 23, 2015)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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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: SCV000271586.2
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
The p.Ala163Val variant in CLDN14 has been previously reported by our laboratory in 1 individual with hearing loss; however, a variant affecting the remaining c … (more)
The p.Ala163Val variant in CLDN14 has been previously reported by our laboratory in 1 individual with hearing loss; however, a variant affecting the remaining c opy of CLDN14 was not identified (LMM unpublished data). The variant has been id entified in 29/66382 European chromosomes by the Exome Aggregation Consortium (E xAC, http://exac.broadinstitute.org; dbSNP rs143797113). Although this variant h as been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is no t predictive enough to determine pathogenicity. In summary, the clinical signifi cance of the p.Ala163Val variant is uncertain. (less)
Number of individuals with the variant: 2
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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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A common variant in CLDN14 causes precipitous, prelingual sensorineural hearing loss in multiple families due to founder effect. | Pater JA | Human genetics | 2017 | PMID: 27838790 |
Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. | Sloan-Heggen CM | Human genetics | 2016 | PMID: 26969326 |
Frequency of rare allelic variation in candidate genes among individuals with low and high urinary calcium excretion. | Toka HR | PloS one | 2013 | PMID: 23991001 |
Text-mined citations for rs143797113 ...
HelpRecord last updated Mar 11, 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.