This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
ClinVar Genomic variation as it relates to human health
NM_012073.5(CCT5):c.440A>G (p.His147Arg)
Germline
Classification
Help
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.
(5)
Help
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.
Uncertain significance
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_012073.5(CCT5):c.440A>G (p.His147Arg)
Variation ID: 1327 Accession: VCV000001327.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5p15.2 5: 10256063 (GRCh38) [ NCBI UCSC ] 5: 10256175 (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 4, 2013 Oct 8, 2024 Jan 19, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_012073.5:c.440A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_036205.1:p.His147Arg missense NM_001306153.1:c.377A>G NP_001293082.1:p.His126Arg missense NM_001306154.2:c.275A>G NP_001293083.1:p.His92Arg missense NM_001306155.2:c.161A>G NP_001293084.1:p.His54Arg missense NM_001306156.2:c.326A>G NP_001293085.1:p.His109Arg missense NM_012073.4:c.440A>G NC_000005.10:g.10256063A>G NC_000005.9:g.10256175A>G NG_012160.1:g.10894A>G LRG_361:g.10894A>G LRG_361t1:c.440A>G P48643:p.His147Arg - Protein change
- H147R, H126R, H54R, H92R, H109R
- Other names
- -
- Canonical SPDI
- NC_000005.10:10256062:A:G
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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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0.00060 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00010
The Genome Aggregation Database (gnomAD) 0.00040
1000 Genomes Project 0.00060
1000 Genomes Project 30x 0.00062
Trans-Omics for Precision Medicine (TOPMed) 0.00075
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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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| CCT5 | - | - |
GRCh38 GRCh37 |
314 | 417 | |
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. |
|---|---|---|---|---|
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jan 19, 2024 | RCV000001390.14 | |
| no classifications from unflagged records (1) |
no classifications from unflagged records
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Dec 7, 2023 | RCV000434241.2 | |
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CCT5-related disorder
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Uncertain significance (1) |
no assertion criteria provided
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Jan 4, 2024 | RCV003952334.2 |
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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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hereditary sensory and autonomic neuropathy with spastic paraplegia
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001318129.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Jan 19, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary sensory and autonomic neuropathy with spastic paraplegia
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001216507.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 147 of the CCT5 protein (p.His147Arg). … (more)
This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 147 of the CCT5 protein (p.His147Arg). This variant is present in population databases (rs118203986, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive mutilating sensory neuropathy with spastic paraplegia (PMID: 16399879). ClinVar contains an entry for this variant (Variation ID: 1327). 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 not expected to disrupt CCT5 protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CCT5 function (PMID: 25124038, 25345891, 28623285, 29552646). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Pathogenic
(May 01, 2006)
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no assertion criteria provided
Method: literature only
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NEUROPATHY, HEREDITARY SENSORY, WITH SPASTIC PARAPLEGIA, AUTOSOMAL RECESSIVE (1 family)
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000021540.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 01, 2024 |
Comment on evidence:
In 4 affected members of a Moroccan family with autosomal recessive mutilating sensory neuropathy with spastic paraplegia (256840), Bouhouche et al. (2006) identified a homozygous … (more)
In 4 affected members of a Moroccan family with autosomal recessive mutilating sensory neuropathy with spastic paraplegia (256840), Bouhouche et al. (2006) identified a homozygous 492A-G transition in exon 4 of the CCT5 gene, resulting in a his147-to-arg (H147R) substitution in the equatorial domain-1 region of the protein. The mutation was not identified in 384 ethnically matched control chromosomes. Variant Function Using recombinant proteins expressed in E. coli, Sergeeva et al. (2014) showed that the H147R mutation did not affect CCT5 stability or structure. Futher analysis showed that the H147R mutation did not affect the ability of CCT5 to hydrolyze ATP, but that it caused a defect in CCT5 chaperonin function. Min et al. (2014) found that human CCT5 and its Pyrococcus furiosus ortholog, which share 44% amino acid identity, exhibit overall structural similarity and characteristic features of group II chaperonins, especially around the equatorial domain. This domain comprises the ATP/ADP-binding site and contains H147 in human and the corresponding residue ile138 (I138) in P. furiosus. Structural analysis indicated that the H147R mutation in human, and the corresponding I138R mutation in P. furiosus, likely impedes the conformational change necessary for ATP binding. Further analysis of the P. furiosus I138R mutant suggested that CCT5 with H147R has impaired oligomeric assembly and ATPase activity and defective protein homeostasis functions. Using differential scanning calorimetry and isothermal titration calorimetry, Spigolon et al. (2017) analyzed structural stability of P. furiosus Cct5 with the I138R mutation (corresponding to human H147R) compared with wildtype Cct5 and Cct5 with an I138H mutation. Wildtype Cct5 had the highest structural stability, and at increasing temperatures, unfolding of the 3 proteins was coupled with dissociation of the oligomers with no intermediate states. All 3 proteins bound ATP, but Cct5 I138R had an exothermic binding enthalpy, whereas wildtype Cct5 and Cct5 I138H had endothermic transitions. Only nucleotide endothermic binding to wildtype Cct5 or Cct5 I138H led to conformational changes induced by Mg-ATP. Circular dichroism confirmed this finding and showed that the 3 proteins underwent conformational changes upon ATP binding. Wildtype Cct5 and Cct5 I138H became more structured upon ATP binding, indicating transition of the complex to the closed conformation. In contrast, upon ATP binding, Cct5 I138R lost structure and resembled the denatured state, confirming that it was energetically the weakest at maintaining the oligomeric complex. Pereira et al. (2017) determined the crystal structure of human CCT5 with the H147R mutation at 3.6-angstrom resolution. The structure showed that the mutation did not affect the oligomeric assembly capability of the homooctameric ring of CCT5. Moreover, the mutation appeared unlikely to impair oligomeric assembly of the full TRIC complex. CCT5-H147R in complex with nucleotide ADP showed nucleotide binding similar to that of wildtype CCT5, consistent with previous observations that H147R mutation did not impair CCT5 ATP hydrolysis. Further analysis suggested that the H147R mutation impacts the function of the entire complex by changing cooperativity within TRIC. (less)
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Uncertain significance
(Jan 04, 2024)
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no assertion criteria provided
Method: clinical testing
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CCT5-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004774907.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The CCT5 c.440A>G variant is predicted to result in the amino acid substitution p.His147Arg. This variant has been reported in the homozygous state in multiple … (more)
The CCT5 c.440A>G variant is predicted to result in the amino acid substitution p.His147Arg. This variant has been reported in the homozygous state in multiple family members with neuropathy and spastic paraplegia (Figure 1, Bouhouche et al. 2006. PubMed ID: 16399879). This variant is reported in 0.056% of alleles in individuals of Latino descent in gnomAD. The results of in vitro experimental studies of this variant are inconclusive (Sergeeva et al. 2014. PubMed ID: 25124038; Min et al. 2014. PubMed ID: 25345891; Pereira et al. 2017. PubMed ID: 28623285; Spigolon et al. 2017. PubMed ID: 29552646). Although we suspect that this variant may be pathogenic, 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 pathogenic
(Oct 06, 2016)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Claim with insufficient supporting evidence
Source: ClinGen
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000521259.4
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
The H147R variant in the CCT5 gene has been reported previously in the homozygous state in four brothers with mutilating sensory neuropathy and spastic paraplegia … (more)
The H147R variant in the CCT5 gene has been reported previously in the homozygous state in four brothers with mutilating sensory neuropathy and spastic paraplegia (Bouhouche et al., 2006). The H147R variant was not observed in approximately 6500 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 H147R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, we interpret H147R as a likely pathogenic variant, (less)
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| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 147 of the CCT5 protein (p.His147Arg). This variant is present in population databases (rs118203986, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive mutilating sensory neuropathy with spastic paraplegia (PMID: 16399879). ClinVar contains an entry for this variant (Variation ID: 1327). 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 not expected to disrupt CCT5 protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CCT5 function (PMID: 25124038, 25345891, 28623285, 29552646). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
The CCT5 c.440A>G variant is predicted to result in the amino acid substitution p.His147Arg. This variant has been reported in the homozygous state in multiple family members with neuropathy and spastic paraplegia (Figure 1, Bouhouche et al. 2006. PubMed ID: 16399879). This variant is reported in 0.056% of alleles in individuals of Latino descent in gnomAD. The results of in vitro experimental studies of this variant are inconclusive (Sergeeva et al. 2014. PubMed ID: 25124038; Min et al. 2014. PubMed ID: 25345891; Pereira et al. 2017. PubMed ID: 28623285; Spigolon et al. 2017. PubMed ID: 29552646). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Comment:
The H147R variant in the CCT5 gene has been reported previously in the homozygous state in four brothers with mutilating sensory neuropathy and spastic paraplegia (Bouhouche et al., 2006). The H147R variant was not observed in approximately 6500 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 H147R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, we interpret H147R as a likely pathogenic variant,
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. |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 147 of the CCT5 protein (p.His147Arg). This variant is present in population databases (rs118203986, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive mutilating sensory neuropathy with spastic paraplegia (PMID: 16399879). ClinVar contains an entry for this variant (Variation ID: 1327). 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 not expected to disrupt CCT5 protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CCT5 function (PMID: 25124038, 25345891, 28623285, 29552646). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
The CCT5 c.440A>G variant is predicted to result in the amino acid substitution p.His147Arg. This variant has been reported in the homozygous state in multiple family members with neuropathy and spastic paraplegia (Figure 1, Bouhouche et al. 2006. PubMed ID: 16399879). This variant is reported in 0.056% of alleles in individuals of Latino descent in gnomAD. The results of in vitro experimental studies of this variant are inconclusive (Sergeeva et al. 2014. PubMed ID: 25124038; Min et al. 2014. PubMed ID: 25345891; Pereira et al. 2017. PubMed ID: 28623285; Spigolon et al. 2017. PubMed ID: 29552646). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Comment:
The H147R variant in the CCT5 gene has been reported previously in the homozygous state in four brothers with mutilating sensory neuropathy and spastic paraplegia (Bouhouche et al., 2006). The H147R variant was not observed in approximately 6500 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 H147R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, we interpret H147R as a likely pathogenic variant,
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Quantitative analysis of the impact of a human pathogenic mutation on the CCT5 chaperonin subunit using a proxy archaeal ortholog. | Spigolon D | Biochemistry and biophysics reports | 2017 | PMID: 29552646 |
| Structure of the human TRiC/CCT Subunit 5 associated with hereditary sensory neuropathy. | Pereira JH | Scientific reports | 2017 | PMID: 28623285 |
| A human CCT5 gene mutation causing distal neuropathy impairs hexadecamer assembly in an archaeal model. | Min W | Scientific reports | 2014 | PMID: 25345891 |
| Biochemical characterization of mutants in chaperonin proteins CCT4 and CCT5 associated with hereditary sensory neuropathy. | Sergeeva OA | The Journal of biological chemistry | 2014 | PMID: 25124038 |
| Mutation in the epsilon subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct5) gene causes autosomal recessive mutilating sensory neuropathy with spastic paraplegia. | Bouhouche A | Journal of medical genetics | 2006 | PMID: 16399879 |
Text-mined citations for rs118203986 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 13, 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.