ClinVar Genomic variation as it relates to human health
NM_153700.2(STRC):c.4171C>G (p.Arg1391Gly)
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_153700.2(STRC):c.4171C>G (p.Arg1391Gly)
Variation ID: 165311 Accession: VCV000165311.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q15.3 15: 43604408 (GRCh38) [ NCBI UCSC ] 15: 43896606 (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 Jan 30, 2015 Jan 6, 2024 Oct 10, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_153700.2:c.4171C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_714544.1:p.Arg1391Gly missense NC_000015.10:g.43604408G>C NC_000015.9:g.43896606G>C NG_011636.1:g.19393C>G - Protein change
- R1391G
- Other names
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- Canonical SPDI
- NC_000015.10:43604407:G:C
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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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0.00020 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00009
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
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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STRC | - | - |
GRCh38 GRCh37 |
235 | 283 |
Conditions - Germline
Condition
Help
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
Help
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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Likely pathogenic (1) |
criteria provided, single submitter
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Jan 10, 2020 | RCV000151950.7 | |
Pathogenic (1) |
no assertion criteria provided
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Feb 19, 2016 | RCV000225023.3 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 25, 2022 | RCV000494575.4 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 7, 2021 | RCV002467597.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 10, 2023 | RCV003398799.1 |
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
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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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Likely pathogenic
(Sep 17, 2015)
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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: SCV000582279.3
First in ClinVar: Jul 02, 2017 Last updated: Jul 02, 2017 |
Comment:
The R1391G variant in the STRC gene has been reported previously in the homozygous and compound heterozygous state, along with a large STRC deletion, in … (more)
The R1391G variant in the STRC gene has been reported previously in the homozygous and compound heterozygous state, along with a large STRC deletion, in multiple individuals with mild to moderate nonsyndromic bilateral sensorineural hearing loss (Francey et al., 2012). The R1391G variant was not observed at any significant frequency in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1391G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The R1391G variant is a strong candidate for a disease-causing variant, however the possibility it may be a rare benign variant cannot be excluded (less)
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Likely pathogenic
(Jan 10, 2020)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000200483.6
First in ClinVar: Jan 30, 2015 Last updated: Jul 03, 2020 |
Comment:
The p.Arg1391Gly variant in STRC has been reported in two Ashkenazi Jewish families with mild to moderate sensorineural hearing loss (Francey 2011). In one family, … (more)
The p.Arg1391Gly variant in STRC has been reported in two Ashkenazi Jewish families with mild to moderate sensorineural hearing loss (Francey 2011). In one family, this variant was found in the homozygous state in all six affected siblings while unaffected parents were heterozygous for this variant. In the other family, the two affected siblings were compound heterozygous for the Arg1391Gly variant and a large deletion of the STRC gene. This variant has also been detected in 0.5% (1/182) of Ashkenazi Jewish control chromosomes by the same study (Francey 2011) and in 0.2% (20/9068) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). In summary, although additional studies are required to fully establish its clinical significance, this variant is classified as likely pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PM3, PP1_Strong, BS1_Supporting. (less)
Number of individuals with the variant: 2
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 16
Affected status: unknown
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002762988.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Likely pathogenic
(Jan 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 16
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center
Accession: SCV004037365.1
First in ClinVar: Sep 30, 2023 Last updated: Sep 30, 2023 |
Comment:
The c.4171C>G variant in the STRC gene is missense variant, which results in the substitution of an arginine residue at amino acid position 1391 for … (more)
The c.4171C>G variant in the STRC gene is missense variant, which results in the substitution of an arginine residue at amino acid position 1391 for a glycine (NP_116023.2). This variant localizes to coding exon 21 of the STRC gene (29 coding exons in total; NM_032634.4). In silico predictors for this variant are not consistent: It is predicted to be neutral to protein structure and/or function by PROVEAN, but is predicted to be damaging by SIFT. This variant was reported in Genome Aggregation Database (gnomAD) with an allelic frequency of 0.0129% (25 out of 193,244 alleles). This variant is reported in ClinVar as pathogenic/likely pathogenic by three laboratories (allele ID# 165311, last accessed 8/11/2020). This variant has been reported in two Ashkenazi Jewish families with mild to moderate hearing loss: in one family, the variant was found in the homozygous state in all six affected siblings while parents were heterozygous carriers. In the second family, two affected siblings were compound heterozygous for this variant and a large deletion of the STRC gene (PMID: 22147502). Given this evidence, the c.4171C>G (p.Arg1391Gly) variant in STRC is considered likely pathogenic. Parental studies were not conducted at our laboratory, but this variant was reported to be paternally-inherited in an older sibling (less)
Clinical Features:
Congenital sensorineural hearing impairment (present)
Family history: yes
Age: 0-9 years
Sex: male
Ethnicity/Population group: Ashkenazi Jew
Tissue: peripheral blood
Comment on evidence:
Observed in trans with c.3275G>A
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Pathogenic
(Oct 10, 2023)
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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: SCV004122714.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
Variant summary: STRC c.4171C>G (p.Arg1391Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: STRC c.4171C>G (p.Arg1391Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 193244 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in STRC causing Nonsyndromic Hearing Loss And Deafness, Type 16 (0.00013 vs 0.0011), allowing no conclusion about variant significance. c.4171C>G has been reported in the literature in multiple individuals affected with Nonsyndromic Hearing Loss And Deafness (Francey_2012, Sloan-Heggen_2016) and observed to segregate with disease. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22147502, 26969326). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Feb 25, 2022)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004225751.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PM2, PM3_strong
Number of individuals with the variant: 3
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Pathogenic
(Feb 19, 2016)
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no assertion criteria provided
Method: research
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Autosomal dominant nonsyndromic hearing loss 16
Affected status: yes
Allele origin:
germline
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Laboratory of Prof. Karen Avraham, Tel Aviv University
Accession: SCV000282018.1
First in ClinVar: Jun 16, 2016 Last updated: Jun 16, 2016 |
Comment:
Congenital, mild-moderate HL
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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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Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. | Sloan-Heggen CM | Human genetics | 2016 | PMID: 26969326 |
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 rs376104748 ...
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.