ClinVar Genomic variation as it relates to human health
NM_153700.2(STRC):c.4917_4918delinsCT (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.
Pathogenic(1); Likely pathogenic(1); Uncertain significance(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.4917_4918delinsCT (p.Leu1640Phe)
Variation ID: 165301 Accession: VCV000165301.14
- Type and length
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Indel, 2 bp
- Location
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Cytogenetic: 15q15.3 15: 43600609-43600610 (GRCh38) [ NCBI UCSC ] 15: 43892807-43892808 (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 Jul 5, 2015 Sep 7, 2023 Aug 24, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_153700.2:c.4917_4918delACinsCT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NC_000015.10:g.43600609_43600610delinsAG NC_000015.9:g.43892807_43892808delinsAG NG_011636.1:g.23191_23192delinsCT - Protein change
- Other names
- rs2920791
- Canonical SPDI
- NC_000015.10:43600608:GT:AG
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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.
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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
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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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STRC | - | - |
GRCh38 GRCh37 |
235 | 283 |
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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Oct 11, 2019 | RCV000151940.7 | |
Pathogenic (2) |
criteria provided, single submitter
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Apr 3, 2019 | RCV000185573.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 24, 2023 | RCV001575950.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 19, 2022 | RCV002516055.1 |
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
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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
(Oct 11, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000200473.6
First in ClinVar: Feb 02, 2015 Last updated: Jul 03, 2020 |
Comment:
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Leu1640Phe variant in STRC has been previously reported in 9 individuals with hearing loss, 7 of … (more)
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Leu1640Phe variant in STRC has been previously reported in 9 individuals with hearing loss, 7 of whom were compound heterozygous for a second pathogenic STRC variant (Mandelker 2014, Vona 2016, LMM unpublished data). One individual was homozygous for this variant, but a different nonsense variant was also identified in the homozygous state in this individual, indicating that the variants were in cis (LMM unpublished data). This variant has also been identified in 0.2% (256/128964) of European chromosomes (including 5 homozygotes) by the Genome Aggregation Database (gnomAD; http://gnomad.broadinstitute.org/; dbSNP rs2860666 and rs2920791). Please note that the Genome Aggregation Database has listed this variant as two separate single nucleotide variants (see rs2860666 and rs2920791) but it was confirmed that the variants occur on the same allele in individuals reported in this database, which is consistent with the variant and amino acid change reported here. Computational prediction tools and conservation analysis suggest that the p.Leu1640Phe variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain due to its relative high frequency in the general population database, including 5 individuals who were homozygous. ACMG/AMP Criteria applied: BS1_Supporting, PM3, BP2. (less)
Number of individuals with the variant: 11
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Pathogenic
(Apr 03, 2019)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 16
Affected status: yes
Allele origin:
maternal
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Center of Genomic medicine, Geneva, University Hospital of Geneva
Accession: SCV001745840.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
This patient harbours a compound heterozygous CKMT1B, STRC,CATSPER2 deletion and a pathogenic variant in STRC
Number of individuals with the variant: 2
Age: 0-9 years
Sex: male
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Likely pathogenic
(Dec 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003656783.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The c.4917_4918delACinsCT (p.L1640F) alteration, located in exon 26 (coding exon 26) of the STRC gene, consists of an in-frame substitution of 2 nucleotides from position … (more)
The c.4917_4918delACinsCT (p.L1640F) alteration, located in exon 26 (coding exon 26) of the STRC gene, consists of an in-frame substitution of 2 nucleotides from position 4917 to 4918, causing the leucine (L) at amino acid position 1640 to be replaced by a phenylalanine (F). Based on data from gnomAD, the CT allele has an overall frequency of 0.117% (331/282340) total alleles studied. The highest observed frequency was 0.199% (256/128964) of European (non-Finnish) alleles. Allele frequencies in general population databases may be unreliable due to high homology with the STRCP1 pseudogene (Vona, 2015; Mandelker, 2014; Francey, 2012). This variant has been observed in trans with a second STRC pathogenic variant in multiple individuals with congenital hearing loss (Back, 2019; Sheppard, 2018; Vona, 2015; Mandelker, 2014). In addition, this variant has been observed as part of a pathogenic gene conversion event in trans with a second STRC variant in one individual with congenital bilateral sensorineural hearing loss (Conlin, 2022). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Aug 24, 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: SCV001803044.2
First in ClinVar: Aug 21, 2021 Last updated: Sep 07, 2023 |
Comment:
In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25157971, 26011646, 30245029, 29907799, … (more)
In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25157971, 26011646, 30245029, 29907799, 36086952, 24963352, 30531641, 34440452, 36190904, 36979683) (less)
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Uncertain significance
(May 23, 2015)
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no assertion criteria provided
Method: research
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Deafness, autosomal recessive 16
Affected status: yes
Allele origin:
maternal
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Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000238473.1 First in ClinVar: Jul 05, 2015 Last updated: Jul 05, 2015 |
Comment:
The heterozygous variant was identified in the STRC gene (c.4917_4918delinsCT; p.Leu1640Phe) is considered a variant of uncertain significance. This variant affects a highly conserved amino … (more)
The heterozygous variant was identified in the STRC gene (c.4917_4918delinsCT; p.Leu1640Phe) is considered a variant of uncertain significance. This variant affects a highly conserved amino acid and has been previously published in 3 affected individuals (PMID: 2157971). This variant is also present in 131 alleles in the ExAC database, out of 121110 total alleles sequenced at this position. (less)
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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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Long-read sequencing for molecular diagnostics in constitutional genetic disorders. | Conlin LK | Human mutation | 2022 | PMID: 36086952 |
Phenotypic Characterization of DFNB16-associated Hearing Loss. | Back D | Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology | 2019 | PMID: 30531641 |
Genomic Landscape and Mutational Signatures of Deafness-Associated Genes. | Azaiez H | American journal of human genetics | 2018 | PMID: 30245029 |
Utility and limitations of exome sequencing as a genetic diagnostic tool for children with hearing loss. | Sheppard S | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29907799 |
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 |
Copy number variants are a common cause of non-syndromic hearing loss. | Shearer AE | Genome medicine | 2014 | PMID: 24963352 |
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 rs727503441 ...
HelpRecord last updated Oct 15, 2023
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.