ClinVar Genomic variation as it relates to human health
NM_000441.2(SLC26A4):c.554G>C (p.Arg185Thr)
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_000441.2(SLC26A4):c.554G>C (p.Arg185Thr)
Variation ID: 188878 Accession: VCV000188878.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q22.3 7: 107674302 (GRCh38) [ NCBI UCSC ] 7: 107314747 (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 Mar 29, 2015 Feb 14, 2024 Jun 24, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000441.2(SLC26A4):c.554G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000441.2:c.554G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000432.1:p.Arg185Thr missense NC_000007.14:g.107674302G>C NC_000007.13:g.107314747G>C NG_008489.1:g.18668G>C O43511:p.Arg185Thr - Protein change
- R185T
- Other names
- NM_000441.1(SLC26A4):c.554G>C(p.Arg185Thr)
- Canonical SPDI
- NC_000007.14:107674301: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 (C)
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00009
Exome Aggregation Consortium (ExAC) 0.00011
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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
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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SLC26A4 | - | - |
GRCh38 GRCh37 |
1335 | 1530 |
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
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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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Likely pathogenic (4) |
reviewed by expert panel
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Jun 24, 2020 | RCV000169232.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 4, 2016 | RCV000214962.4 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Oct 26, 2023 | RCV000677335.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 15, 2018 | RCV000778810.4 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 8, 2024 | RCV001850394.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 27, 2021 | RCV002498842.1 |
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
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
(Jun 24, 2020)
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reviewed by expert panel
Method: curation
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Pendred syndrome
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Hearing Loss Variant Curation Expert Panel
Accession: SCV001428425.1
First in ClinVar: Aug 15, 2020 Last updated: Aug 15, 2020 |
Comment:
The c.554G>A (p.Arg185Thr) variant in SLC26A4 was present in 0.03287% (1/3042) of South Asian alleles in gnomAD v3, which is a low enough frequency to … (more)
The c.554G>A (p.Arg185Thr) variant in SLC26A4 was present in 0.03287% (1/3042) of South Asian alleles in gnomAD v3, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined for autosomal recessive hearing loss by the ClinGen Hearing Loss Expert Panel (PM2_Supporting; gnomad.broadinstitute.org). This variant has been identified in one individual with unilateral hearing loss and enlarged vestibular aqueduct with a second likely pathogenic variant in trans, as well as two probands without a second variant identified but whose phenotypes were consistent with Pendred syndrome (PM3, PP4; PMID: 24051746, 20597900, 22285650). It was also observed in one proband with limited phenotype information and no second variant identified (PMID: 31387071). Functional evidence demonstrates that the p.Arg185Thr variant may impact protein function (PS3_Supporting, PMID: 22285650, 24051746). The REVEL computational prediction tool produced a score of 0.876, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM3, PS3_Supporting, PM2_Supporting, PP3, PP4. (less)
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Pathogenic
(Jan 04, 2016)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000271454.3
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
The p.Arg185Thr variant in SLC26A4 has been previously reported in three individ uals with hearing loss and enlarged vestibular aqueducts, including one individu al who … (more)
The p.Arg185Thr variant in SLC26A4 has been previously reported in three individ uals with hearing loss and enlarged vestibular aqueducts, including one individu al who was compound heterozygous for a second pathogenic variant in the SLC26A4 gene (Chattaraj 2013, Cirello 2012, Pourova 2010). This variant has been identif ied in 12/66734 (0.02%) of European chromosomes by the Exome Aggregation Consort ium (ExAC, http://exac.broadinstitute.org; dbSNP rs542620119); however, this fre quency is low enough to be consistent with a recessive carrier frequency. In vit ro functional studies reveal that the variant results in abnormal cellular local ization of the protein and significant reduction in its normal functional activi ty (Cirello 2012, Chattaraj 2013), supporting a deleterious effect for this vari ant. In addition, computational tools and conservation analyses predict that the p.Arg185Thr variant may impact the protein. In summary, this variant meets our criteria to be classified as pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(-)
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criteria provided, single submitter
Method: research
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Pendred syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Otorhinolaryngology Lab - LIM32, University of Sao Paulo School of Medicine Clinics Hospital
Accession: SCV001792214.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Comment:
in compound heterozygosis with the c.412G>T variant in a subject with bilateral non-syndromic sensorineural prelingual hearing loss (sporadic)
Clinical Features:
Prelingual sensorineural hearing impairment (present) , Incomplete partition of the cochlea type II (present) , Enlarged vestibular aqueduct syndrome (present)
Family history: yes
Segregation observed: yes
Secondary finding: no
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Likely pathogenic
(Jul 10, 2014)
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criteria provided, single submitter
Method: literature only
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Pendred's syndrome
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000220501.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Likely pathogenic
(Oct 27, 2021)
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criteria provided, single submitter
Method: clinical testing
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Pendred syndrome
Autosomal recessive nonsyndromic hearing loss 4
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002810544.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Apr 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Pendred syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003928981.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
Variant summary: SLC26A4 c.554G>C (p.Arg185Thr) results in a non-conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547) of the encoded protein sequence. Five … (more)
Variant summary: SLC26A4 c.554G>C (p.Arg185Thr) results in a non-conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547) of 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 9.1e-05 in 251456 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC26A4 causing Pendred Syndrome (9.1e-05 vs 0.0035), allowing no conclusion about variant significance. c.554G>C has been reported in the literature in individuals affected with clinical features of Pendred Syndrome (example, Pourova_2010, Cirello_2012, Chattaraj_2013, Lenarduzzi_2019, Batissoco_2022). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in predominantly intracellular localization and a partial glycosylation defect resulting in impaired chloride and iodide ion transport in-vitro (example, Cirello_2012, Chattaraj_2013). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (LP/P, n=5; VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Oct 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 4
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004201821.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(May 23, 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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Revvity Omics, Revvity
Accession: SCV004238663.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Uncertain significance
(May 31, 2018)
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criteria provided, single submitter
Method: curation
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Autosomal recessive nonsyndromic hearing loss 4
Affected status: unknown
Allele origin:
unknown
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SIB Swiss Institute of Bioinformatics
Accession: SCV000803604.1
First in ClinVar: Aug 20, 2018 Last updated: Aug 20, 2018 |
Comment:
This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for DFNB4, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => … (more)
This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for DFNB4, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3-Supporting => PS3 downgraded in strength to Supporting (PMID:22285650). PM2-Supporting => PM2 downgraded in strength to Supporting. PM3-Supporting => PM3 downgraded in strength to Supporting (PMID:24051746). (less)
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Likely pathogenic
(Aug 15, 2018)
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criteria provided, single submitter
Method: clinical testing
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SLC26A4-Related Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000915190.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The SLC26A4 c.554G>C (p.Arg185Thr) variant is a missense variant that has been reported in a total of three individuals with nonsyndromic hearing loss or Pendred … (more)
The SLC26A4 c.554G>C (p.Arg185Thr) variant is a missense variant that has been reported in a total of three individuals with nonsyndromic hearing loss or Pendred syndrome, including in a compound heterozygous state in one and in a heterozygous state in two (Pourova et al. 2010; Cirello et al. 2012; Chattaraj et al. 2013). One of the heterozygotes was also heterozygous for a missense variant in the FOXI1 gene, which is said to display digenic inheritance with SLC26A4. The p.Arg185Thr variant is reported at a frequency of 0.000180 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in COS-7 cells, HEK293 phoenix cells and Xenopus oocytes have demonstrated the variant results in a trafficking defect, altered maturation, and reduced function compared to wildtype. Based on the collective evidence, the p.Arg185Thr variant is classified as likely pathogenic for SLC26A4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Jan 08, 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: SCV002243689.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 185 of the SLC26A4 protein (p.Arg185Thr). … (more)
This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 185 of the SLC26A4 protein (p.Arg185Thr). This variant is present in population databases (rs542620119, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of Pendred syndrome (PMID: 20597900, 22285650, 24051746, 31387071, 34599368). 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: 188878). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC26A4 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 22285650, 24051746). For these reasons, this variant has been classified as Pathogenic. (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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Molecular and genetic characterization of a large Brazilian cohort presenting hearing loss. | Batissoco AC | Human genetics | 2022 | PMID: 34599368 |
Next generation sequencing study in a cohort of Italian patients with syndromic hearing loss. | Lenarduzzi S | Hearing research | 2019 | PMID: 31387071 |
Use of SLC26A4 mutation testing for unilateral enlargement of the vestibular aqueduct. | Chattaraj P | JAMA otolaryngology-- head & neck surgery | 2013 | PMID: 24051746 |
Molecular and functional studies of 4 candidate loci in Pendred syndrome and nonsyndromic hearing loss. | Cirello V | Molecular and cellular endocrinology | 2012 | PMID: 22285650 |
Spectrum and frequency of SLC26A4 mutations among Czech patients with early hearing loss with and without Enlarged Vestibular Aqueduct (EVA). | Pourová R | Annals of human genetics | 2010 | PMID: 20597900 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/cfc9189b-83ef-4fee-9391-68daefe50667 | - | - | - | - |
Text-mined citations for rs542620119 ...
HelpRecord last updated Apr 06, 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.