ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.1040G>C (p.Arg347Pro)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000492.4(CFTR):c.1040G>C (p.Arg347Pro)
Variation ID: 7110 Accession: VCV000007110.111
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117540270 (GRCh38) [ NCBI UCSC ] 7: 117180324 (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 24, 2015 Jun 17, 2024 Mar 3, 2004 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.1040G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Arg347Pro missense NC_000007.14:g.117540270G>C NC_000007.13:g.117180324G>C NG_016465.4:g.79487G>C LRG_663:g.79487G>C LRG_663t1:c.1040G>C LRG_663p1:p.Arg347Pro P13569:p.Arg347Pro - Protein change
- R347P
- Other names
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- Canonical SPDI
- NC_000007.14:117540269: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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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CFTR | - | - |
GRCh38 GRCh37 |
3729 | 5055 |
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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Pathogenic (11) |
practice guideline
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Mar 3, 2004 | RCV000007530.32 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001004251.9 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Jan 23, 2023 | RCV001530124.22 | |
CFTR-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Mar 17, 2017 | RCV001831520.9 |
Pathogenic (1) |
criteria provided, single submitter
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Mar 3, 2022 | RCV002504761.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 20, 2024 | RCV003473002.2 |
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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pathogenic
(Mar 03, 2004)
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practice guideline
Method: curation
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Cystic fibrosis
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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American College of Medical Genetics and Genomics (ACMG)
Study: The ACMG recommended carrier screening panel
Accession: SCV000071389.2 First in ClinVar: Jun 04, 2013 Last updated: Mar 24, 2015 |
Comment:
Converted during submission to Pathogenic.
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Pathogenic
(Mar 17, 2017)
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reviewed by expert panel
Method: research
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Cystic fibrosis
Affected status: yes
Allele origin:
germline
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CFTR2
Study: CFTR2
Accession: SCV000071521.4 First in ClinVar: Oct 18, 2013 Last updated: Oct 11, 2015 |
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Pathogenic
(Jan 29, 2018)
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criteria provided, single submitter
Method: curation
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cystic fibrosis
Affected status: yes
Allele origin:
germline
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CFTR-France
Accession: SCV001169458.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
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Pathogenic
(Feb 27, 2020)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV001425443.1
First in ClinVar: Aug 03, 2020 Last updated: Aug 03, 2020 |
Comment:
Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
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Pathogenic
(Dec 27, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002699407.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R347P pathogenic mutation (also known as c.1040G>C), located in coding exon 8 of the CFTR gene, results from a G to C substitution at … (more)
The p.R347P pathogenic mutation (also known as c.1040G>C), located in coding exon 8 of the CFTR gene, results from a G to C substitution at nucleotide position 1040. The arginine at codon 347 is replaced by proline, an amino acid with dissimilar properties. This pathogenic mutation has been associated with variable pancreatic sufficiency, variable pulmonary disease, and elevated sweat chloride levels; in addition, functional in vitro studies showed significantly decreased CFTR expression and no chloride conduction (Braun AT et al. J Cyst Fibros. 2006;5(1):33-41; Sosnay PR et al. Nat Genet. 2013;45(10):1160-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Jan 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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005046896.1
First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024 |
Number of individuals with the variant: 2
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Pathogenic
(Jan 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696817.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Comment:
Variant summary: The CFTR c.1040G>C (p.Arg347Pro) variant located in the ABC transporter type 1, transmembrane domain (via InterPro) involves the alteration of a conserved nucleotide, … (more)
Variant summary: The CFTR c.1040G>C (p.Arg347Pro) variant located in the ABC transporter type 1, transmembrane domain (via InterPro) involves the alteration of a conserved nucleotide, which 4/5 in silico tools predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121338, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant of 1/77. Multiple publications have cited the variant in affected individuals, and multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. The variant of interest is a known, well-established common Pathogenic. Therefore, the variant of interest has been classified as "pathogenic." (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Congenital bilateral aplasia of vas deferens from CFTR mutation
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001163127.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
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Pathogenic
(Dec 20, 2019)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV001194235.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_000492.3(CFTR):c.1040G>C(R347P) is classified as pathogenic in the context of cystic fibrosis. Sources cited for classification include the following: PMID 12454843, 23974870, 8535440 and 20448091. Classification … (more)
NM_000492.3(CFTR):c.1040G>C(R347P) is classified as pathogenic in the context of cystic fibrosis. Sources cited for classification include the following: PMID 12454843, 23974870, 8535440 and 20448091. Classification of NM_000492.3(CFTR):c.1040G>C(R347P) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Nov 05, 2018)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: yes
Allele origin:
unknown
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Mendelics
Accession: SCV000886258.2
First in ClinVar: Oct 11, 2015 Last updated: Dec 11, 2022 |
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Pathogenic
(Dec 06, 2021)
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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: SCV000603032.5
First in ClinVar: Sep 30, 2017 Last updated: Dec 24, 2022 |
Comment:
The CFTR c.1040G>C; p.Arg347Pro variant (rs77932196) has been reported in multiple patients diagnosed with cystic fibrosis (Chavez-Saldana 2010, Dean 1990, Ivady 2011) and is associated … (more)
The CFTR c.1040G>C; p.Arg347Pro variant (rs77932196) has been reported in multiple patients diagnosed with cystic fibrosis (Chavez-Saldana 2010, Dean 1990, Ivady 2011) and is associated with both pancreatic-sufficient and -insufficient disease (Dean 1990, Ooi 2012, CFTR2 database). It has also been identified in individuals with congenital bilateral absence of vas deferens and infertility (Amato 2012, Tomaiuolo 2011) when found in-trans with a mildly pathogenic CFTR variant (Tomaiuolo 2011). Functional characterization of the p.Arg347Pro variant protein indicates a failure to generate mature protein, leading to the loss of chloride transport activity (Sosnay 2013, Van Goor 2014). The variant is listed as pathogenic in ClinVar (Variation ID: 7110) and is observed twice in the Exome Variant Server (2/13006 alleles) and 6 times in the Genome Aggregation Database (6/245866 alleles). The arginine at residue 347 is highly conserved (Alamut v2.10), and computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that this variant is deleterious. Based on the above information, p.Arg347Pro variant is classified as moderately pathogenic. References: CFTR2 database: https://www.cftr2.org/ Amato F et al. Extensive molecular analysis of patients bearing CFTR-related disorders. J Mol Diagn. 2012; 14(1):81-9. Chavez-Saldana M et al. CFTR allelic heterogeneity in Mexican patients with cystic fibrosis: implications for molecular screening. Rev Invest Clin. 2010; 62(6):546-52. Dean M et al. Multiple mutations in highly conserved residues are found in mildly affected cystic fibrosis patients. Cell. 1990; 61(5):863-70. Ivady G et al. Distribution of CFTR mutations in Eastern Hungarians: relevance to genetic testing and to the introduction of newborn screening for cystic fibrosis. J Cyst Fibros. 2011; 10(3):217-20. Ooi C. et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012; 11(5):355-62. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7. Tomaiuolo R et al. Enhanced frequency of CFTR gene variants in couples who are candidates for assisted reproductive technology treatment. Clin Chem Lab Med. 2011; 49(8):1289-93. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014; 13(1):29-36. (less)
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Pathogenic
(Mar 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary pancreatitis
Bronchiectasis with or without elevated sweat chloride 1 Cystic fibrosis Congenital bilateral aplasia of vas deferens from CFTR mutation
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002799274.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jan 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002046175.2
First in ClinVar: Jan 03, 2022 Last updated: Jan 06, 2024 |
Comment:
This variant has been reported in individuals affected with Cystic Fibrosis in the published literature (PMID: 15371902 (2004), 32429104 (2020), 31523618 (2019), 22658665 (2012), 20448091 … (more)
This variant has been reported in individuals affected with Cystic Fibrosis in the published literature (PMID: 15371902 (2004), 32429104 (2020), 31523618 (2019), 22658665 (2012), 20448091 (2010)). Functional studies have shown that this variant results in defective CFTR protein maturation and protein conductance (PMID: 24440181 (2014), 23891399 (2014), 23974870 (2013)). Therefore, the variant is classified as pathogenic. (less)
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Pathogenic
(Dec 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001588862.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 347 of the CFTR protein (p.Arg347Pro). … (more)
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 347 of the CFTR protein (p.Arg347Pro). This variant is present in population databases (rs77932196, gnomAD 0.005%). This missense change has been observed in individual(s) with cystic fibrosis and congenital absence of the vas deferns (PMID: 1723032, 2344617, 10376575, 12400067, 31523618). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7110). 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 CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 23891399, 23974870). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 20, 2024)
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criteria provided, single submitter
Method: clinical testing
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Bronchiectasis with or without elevated sweat chloride 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004213331.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Jan 01, 1991)
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no assertion criteria provided
Method: literature only
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CYSTIC FIBROSIS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000027731.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 11, 2015 |
Comment on evidence:
In 3 sibs with cystic fibrosis (CF; 219700) from a family identified as UT 1446, Dean et al. (1990) found a C-to-G transversion at position … (more)
In 3 sibs with cystic fibrosis (CF; 219700) from a family identified as UT 1446, Dean et al. (1990) found a C-to-G transversion at position 1172 in the CFTR gene, resulting in substitution of proline for aspartic acid (R347P). The mutation destroyed a HhaI restriction site and created a NcoI site. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001744798.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956542.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001971843.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Pathogenic
(Mar 17, 2017)
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no assertion criteria provided
Method: clinical testing
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CFTR-related disorders
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002078183.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
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not provided
(-)
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no classification provided
Method: literature only
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Cystic fibrosis
Affected status: unknown
Allele origin:
unknown
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GeneReviews
Accession: SCV001622786.2
First in ClinVar: May 23, 2021 Last updated: Oct 01, 2022 |
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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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Analysis of CFTR Mutation Spectrum in Ethnic Russian Cystic Fibrosis Patients. | Petrova NV | Genes | 2020 | PMID: 32429104 |
Cystic Fibrosis Mutation Spectrum in North Macedonia: A Step Toward Personalized Therapy. | Terzic M | Balkan journal of medical genetics : BJMG | 2019 | PMID: 31523618 |
The relative frequency of CFTR mutation classes in European patients with cystic fibrosis. | De Boeck K | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2014 | PMID: 24440181 |
Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. | Van Goor F | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2014 | PMID: 23891399 |
Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. | Sosnay PR | Nature genetics | 2013 | PMID: 23974870 |
Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. | Ooi CY | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2012 | PMID: 22658665 |
Enhanced frequency of CFTR gene variants in couples who are candidates for assisted reproductive technology treatment. | Tomaiuolo R | Clinical chemistry and laboratory medicine | 2011 | PMID: 21679131 |
Effects of gender and age at diagnosis on disease progression in long-term survivors of cystic fibrosis. | Nick JA | American journal of respiratory and critical care medicine | 2010 | PMID: 20448091 |
Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations and risk for pancreatic adenocarcinoma. | McWilliams RR | Cancer | 2010 | PMID: 19885835 |
Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. | Castellani C | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2008 | PMID: 18456578 |
Cystic fibrosis mutations and genotype-pulmonary phenotype analysis. | Braun AT | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2006 | PMID: 16275171 |
Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel. | Watson MS | Genetics in medicine : official journal of the American College of Medical Genetics | 2004 | PMID: 15371902 |
Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study. | McKone EF | Lancet (London, England) | 2003 | PMID: 12767731 |
Genotype and phenotype correlations in patients with cystic fibrosis and pancreatitis. | Durno C | Gastroenterology | 2002 | PMID: 12454843 |
A cystic fibrosis patient with two novel mutations in mitochondrial DNA: mild disease led to delayed diagnosis of both disorders. | Wong LJ | American journal of medical genetics | 2002 | PMID: 12400067 |
Proportion of cystic fibrosis gene mutations not detected by routine testing in men with obstructive azoospermia. | Mak V | JAMA | 1999 | PMID: 10376575 |
Pancreatic insufficiency and pulmonary disease in German and Slavic cystic fibrosis patients with the R347P mutation. | Varon R | Human mutation | 1995 | PMID: 8535440 |
Hereditary disorders in Saguenay-Lac-St-Jean (Quebec, Canada). | De Braekeleer M | Human heredity | 1991 | PMID: 1937486 |
Nine mutations in the cystic fibrosis (CF) gene account for 80% of the CF chromosomes in French patients. | Simon-Bouy B | Clinical genetics | 1991 | PMID: 1723032 |
Multiple mutations in highly conserved residues are found in mildly affected cystic fibrosis patients. | Dean M | Cell | 1990 | PMID: 2344617 |
https://cftr2.org | - | - | - | - |
https://cftr2.org/mutation/scientific/R347P/ | - | - | - | - |
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Text-mined citations for rs77932196 ...
HelpRecord last updated Jul 07, 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.