ClinVar Genomic variation as it relates to human health
NM_153700.2(STRC):c.4918C>T (p.Leu1640Phe)
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.
Likely pathogenic(1); Uncertain significance(2); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_153700.2(STRC):c.4918C>T (p.Leu1640Phe)
Variation ID: 417924 Accession: VCV000417924.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q15.3 15: 43600609 (GRCh38) [ NCBI UCSC ] 15: 43892807 (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 Apr 23, 2017 Apr 15, 2024 Jan 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_153700.2:c.4918C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_714544.1:p.Leu1640Phe missense NC_000015.10:g.43600609G>A NC_000015.9:g.43892807G>A NG_011636.1:g.23192C>T - Protein change
- L1640F
- Other names
- -
- Canonical SPDI
- NC_000015.10:43600608: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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0.00080 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00080
Exome Aggregation Consortium (ExAC) 0.00108
The Genome Aggregation Database (gnomAD), exomes 0.00118
The Genome Aggregation Database (gnomAD) 0.00174
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
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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STRC | - | - |
GRCh38 GRCh37 |
235 | 283 |
Conditions - Germline
Condition
Help
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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Likely pathogenic (2) |
criteria provided, single submitter
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Feb 28, 2023 | RCV000477840.4 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 1, 2024 | RCV000508480.29 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 11, 2023 | RCV003418216.5 |
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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Uncertain significance
(Aug 04, 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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000605315.2
First in ClinVar: Sep 30, 2017 Last updated: Feb 17, 2019 |
Comment:
The p.Leu1640Phe variant (rs727503441) has previously been associated with congenital moderate hearing loss in several patients who also carried heterozygous deletions of STRC (Mandelker 2014 … (more)
The p.Leu1640Phe variant (rs727503441) has previously been associated with congenital moderate hearing loss in several patients who also carried heterozygous deletions of STRC (Mandelker 2014 and Vona 2015). It has also been reported to ClinVar with the classification of uncertain significance. The c.4917_4918delinsCT variant is listed in the Genome Aggregation Database (gnomAD) browser as two separate variants, c.4917A>C and c.4918C>T (rs2860666 and rs2920791), but viewable data on the gnomAD website indicate that both variants are inherited together and have an overall population frequency of 0.118 percent (identified on 289 out of 245,896 chromosomes, including 5 homozygotes). Individuals with hearing loss are not explicitly excluded from the gnomAD data set; therefore, the hearing ability of the 5 homozygous individuals in gnomAD is unknown. The leucine at position 1640 is moderately conserved (considering 11 species) (Alamut v.2.8.1) and computational analyses predict conflicting effects of this variant on protein structure/function (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: possibly damaging). (less)
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Likely benign
(Jun 27, 2019)
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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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Athena Diagnostics Inc
Accession: SCV001145831.1
First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020 |
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Likely pathogenic
(Feb 28, 2023)
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criteria provided, single submitter
Method: research
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Autosomal recessive nonsyndromic hearing loss 16
Affected status: yes
Allele origin:
unknown
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King Laboratory, University of Washington
Accession: SCV003844148.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
This variant occurred in homozygosity in a patient with bilateral sensorineural hearing loss of onset <18 years, in a study of pediatric hearing loss conducted … (more)
This variant occurred in homozygosity in a patient with bilateral sensorineural hearing loss of onset <18 years, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). This patient was born to consanguineous parents and their family has no other history of hearing loss. This variant is a missense at a highly conserved site and is predicted to be damaging by multiple in-silico tools. As of January 2023, this variant has been reported to ClinVar with conflicting interpretations and is found in 331 heterozygotes and 5 homozygotes on gnomAD. Based on homozygosity, consistently predicted functional effect, and goodness of fit of genotype to phenotype, we conclude that this variant is likely pathogenic. (less)
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Uncertain significance
(Dec 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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STRC-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004114226.2
First in ClinVar: Nov 20, 2023 Last updated: Mar 16, 2024 |
Comment:
The STRC c.4918C>T variant is predicted to result in the amino acid substitution p.Leu1640Phe. This variant in exon 26 of the STRC gene corresponds to … (more)
The STRC c.4918C>T variant is predicted to result in the amino acid substitution p.Leu1640Phe. This variant in exon 26 of the STRC gene corresponds to a known STRCP1 pseudogene variant. This variant has been reported in three patients with hearing loss in trans to a STRC full gene deletion, and was confirmed using an assay that excludes the STRCP1 pseudogene in two of these patients (Vona et al. 2015. PubMed ID: 26011646; described as c.4917_4918delinsCT, Mandelker et al. 2014. PubMed ID: 25157971; Table S2, Shearer et al. 2014. PubMed ID: 24963352). This variant is reported in 0.20% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including five homozygotes with unknown hearing status. However, NGS based population database allele frequencies may not be accurate at this locus due to paralogy. Additionally, at PreventionGenetics and using an assay that excludes the STRCP1 pseudogene, we have observed this variant in the hemizygous state in trans to a STRC multi-exon deletion in a patient with hearing loss as well as in the homozygous state in three patients undergoing testing unrelated to hearing loss. This variant is listed in ClinVar with conflicting interpretations of uncertain and likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/417924/). Although we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Likely benign
(Jan 01, 2024)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001500666.17
First in ClinVar: Mar 14, 2021 Last updated: Apr 15, 2024 |
Comment:
STRC: BS2
Number of individuals with the variant: 3
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Uncertain significance
(Apr 07, 2015)
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no assertion criteria provided
Method: research
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Autosomal recessive nonsyndromic hearing loss 16
Affected status: yes
Allele origin:
maternal
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Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000536861.1 First in ClinVar: Apr 23, 2017 Last updated: Apr 23, 2017 |
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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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Association of Genetic Diagnoses for Childhood-Onset Hearing Loss With Cochlear Implant Outcomes. | Carlson RJ | JAMA otolaryngology-- head & neck surgery | 2023 | PMID: 36633841 |
DFNB16 is a frequent cause of congenital hearing impairment: implementation of STRC mutation analysis in routine diagnostics. | Vona B | Clinical genetics | 2015 | PMID: 26011646 |
Comprehensive diagnostic testing for stereocilin: an approach for analyzing medically important genes with high homology. | Mandelker D | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157971 |
Genome-wide SNP genotyping identifies the Stereocilin (STRC) gene as a major contributor to pediatric bilateral sensorineural hearing impairment. | Francey LJ | American journal of medical genetics. Part A | 2012 | PMID: 22147502 |
Text-mined citations for rs2920791 ...
HelpRecord last updated Apr 15, 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.