In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34469436, 34356170, 33880452, Nair_2023_Review, 36252719, 26125038, 21376300, 21820098, 35586607, 32746806, 32935419, 31813911, 28834584)
ClinVar Genomic variation as it relates to human health
NM_001244008.2(KIF1A):c.37C>T (p.Arg13Cys)
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.
(7)
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.
Pathogenic/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001244008.2(KIF1A):c.37C>T (p.Arg13Cys)
Variation ID: 426934 Accession: VCV000426934.36
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q37.3 2: 240797716 (GRCh38) [ NCBI UCSC ] 2: 241737133 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 May 22, 2017 Nov 24, 2024 Dec 27, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001244008.2:c.37C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001230937.1:p.Arg13Cys missense NM_001244008.1:c.37C>T NM_001320705.2:c.37C>T NP_001307634.1:p.Arg13Cys missense NM_001330289.2:c.37C>T NP_001317218.1:p.Arg13Cys missense NM_001330290.2:c.37C>T NP_001317219.1:p.Arg13Cys missense NM_001379631.1:c.37C>T NP_001366560.1:p.Arg13Cys missense NM_001379632.1:c.37C>T NP_001366561.1:p.Arg13Cys missense NM_001379633.1:c.37C>T NP_001366562.1:p.Arg13Cys missense NM_001379634.1:c.37C>T NP_001366563.1:p.Arg13Cys missense NM_001379635.1:c.37C>T NP_001366564.1:p.Arg13Cys missense NM_001379636.1:c.37C>T NP_001366565.1:p.Arg13Cys missense NM_001379637.1:c.37C>T NP_001366566.1:p.Arg13Cys missense NM_001379638.1:c.37C>T NP_001366567.1:p.Arg13Cys missense NM_001379639.1:c.37C>T NP_001366568.1:p.Arg13Cys missense NM_001379640.1:c.37C>T NP_001366569.1:p.Arg13Cys missense NM_001379641.1:c.37C>T NP_001366570.1:p.Arg13Cys missense NM_001379642.1:c.37C>T NP_001366571.1:p.Arg13Cys missense NM_001379645.1:c.37C>T NP_001366574.1:p.Arg13Cys missense NM_001379646.1:c.37C>T NP_001366575.1:p.Arg13Cys missense NM_001379648.1:c.37C>T NP_001366577.1:p.Arg13Cys missense NM_001379649.1:c.37C>T NP_001366578.1:p.Arg13Cys missense NM_001379650.1:c.37C>T NP_001366579.1:p.Arg13Cys missense NM_001379651.1:c.37C>T NP_001366580.1:p.Arg13Cys missense NM_001379653.1:c.37C>T NP_001366582.1:p.Arg13Cys missense NM_004321.8:c.37C>T NP_004312.2:p.Arg13Cys missense NC_000002.12:g.240797716G>A NC_000002.11:g.241737133G>A NG_029724.1:g.27492C>T LRG_367:g.27492C>T - Protein change
- R13C
- Other names
- -
- Canonical SPDI
- NC_000002.12:240797715:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
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- 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. |
|||
| KIF1A | No evidence available | No evidence available |
GRCh38 GRCh37 |
2906 | 3115 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 5, 2023 | RCV000489169.20 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 27, 2023 | RCV001057550.9 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Sep 3, 2018 | RCV001250737.2 | |
|
See cases
|
not provided (1) |
no classification provided
|
- | RCV001568399.2 |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 14, 2023 | RCV003224875.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 17, 2023 | RCV004787796.1 |
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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|---|---|---|---|---|---|
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Likely pathogenic
(Sep 03, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Intellectual disability, autosomal dominant 9
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV001426146.1
First in ClinVar: Aug 02, 2020 Last updated: Aug 02, 2020 |
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Pathogenic
(Feb 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000577515.6
First in ClinVar: May 22, 2017 Last updated: Nov 11, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34469436, 34356170, 33880452, Nair_2023_Review, 36252719, 26125038, 21376300, 21820098, 35586607, 32746806, 32935419, 31813911, 28834584) (less)
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Pathogenic
(Dec 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 30
Neuropathy, hereditary sensory, type 2C Intellectual disability, autosomal dominant 9
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001222048.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 13 of the KIF1A protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 13 of the KIF1A protein (p.Arg13Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant hereditary spastic paraplegia (PMID: 31813911; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 426934). 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 KIF1A protein function with a positive predictive value of 95%. This variant disrupts the p.Arg13 amino acid residue in KIF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28834584). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Likely pathogenic
(May 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002544239.16
First in ClinVar: Jul 09, 2022 Last updated: Oct 20, 2024 |
Comment:
KIF1A: PM2, PM5, PM6:Supporting, PP2, PP3, PP4, PS4:Supporting
Number of individuals with the variant: 1
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Pathogenic
(Apr 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability, autosomal dominant 9
Hereditary spastic paraplegia 30
Affected status: unknown
Allele origin:
de novo
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV003920951.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Method: Exome sequencing
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|
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Pathogenic
(Jul 17, 2023)
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criteria provided, single submitter
Method: clinical testing
|
KIF1A related neurological disorder
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005400165.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Dominant negative has been shown to cause NESCAV syndrome (MIM#614255; OMIM). Both loss and gain of function mechanisms have been reported for variants causing spastic paraplegia 30 (MIM#610357, MIM#610357) and hereditary sensory and autonomic neuropathy type 2 (HSAN2; MIM#614213) (PMIDs: 31488895, 31455732). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. Genotype-phenotype correlation is currently unestablished. Missense variants tend to cluster within the kinesin motor domain and have been reported for both SPG30 and NESCAV syndrome. Only the correlation for HSAN2 (MIM#614213) is established with all patients except for one, carrying null variants outside the motor domain (PMID: 32737135). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated kinesin motor domain (DECIPHER). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Three alternative amino acid substitutions at the same position, p.(Arg13Leu), p.(Arg13Ser) and p.(Arg13His), have been classified as pathogenic or likely pathogenic by clinical laboratories in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by clinical laboratories in ClinVar, and has been observed in several individuals with spastic paraplegia including some de novo occurrences (PMIDs: 31813911, 32746806, 34487232). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
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not provided
(-)
|
no classification provided
Method: research
|
See cases
Affected status: yes
Allele origin:
de novo
|
DECIPHER, Wellcome Sanger Institute
Accession: SCV001754550.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Clinical Features:
Abnormality of head or neck (present) , Abnormality of the nervous system (present) , Abnormality of the integument (present) , abnormality of the musculoskeletal system … (more)
Abnormality of head or neck (present) , Abnormality of the nervous system (present) , Abnormality of the integument (present) , abnormality of the musculoskeletal system (present) , Abnormality of limbs (present) (less)
Comment on evidence:
PM2: moderate, PP2: supporting, PS1: strong, PS2: strong
Testing laboratory: A DECIPHER depositor
Testing laboratory interpretation: Pathogenic
|
Comment:
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 13 of the KIF1A protein (p.Arg13Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant hereditary spastic paraplegia (PMID: 31813911; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 426934). 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 KIF1A protein function with a positive predictive value of 95%. This variant disrupts the p.Arg13 amino acid residue in KIF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28834584). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
KIF1A: PM2, PM5, PM6:Supporting, PP2, PP3, PP4, PS4:Supporting
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Dominant negative has been shown to cause NESCAV syndrome (MIM#614255; OMIM). Both loss and gain of function mechanisms have been reported for variants causing spastic paraplegia 30 (MIM#610357, MIM#610357) and hereditary sensory and autonomic neuropathy type 2 (HSAN2; MIM#614213) (PMIDs: 31488895, 31455732). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. Genotype-phenotype correlation is currently unestablished. Missense variants tend to cluster within the kinesin motor domain and have been reported for both SPG30 and NESCAV syndrome. Only the correlation for HSAN2 (MIM#614213) is established with all patients except for one, carrying null variants outside the motor domain (PMID: 32737135). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated kinesin motor domain (DECIPHER). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Three alternative amino acid substitutions at the same position, p.(Arg13Leu), p.(Arg13Ser) and p.(Arg13His), have been classified as pathogenic or likely pathogenic by clinical laboratories in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by clinical laboratories in ClinVar, and has been observed in several individuals with spastic paraplegia including some de novo occurrences (PMIDs: 31813911, 32746806, 34487232). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
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:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34469436, 34356170, 33880452, Nair_2023_Review, 36252719, 26125038, 21376300, 21820098, 35586607, 32746806, 32935419, 31813911, 28834584)
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 13 of the KIF1A protein (p.Arg13Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant hereditary spastic paraplegia (PMID: 31813911; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 426934). 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 KIF1A protein function with a positive predictive value of 95%. This variant disrupts the p.Arg13 amino acid residue in KIF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28834584). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
KIF1A: PM2, PM5, PM6:Supporting, PP2, PP3, PP4, PS4:Supporting
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Dominant negative has been shown to cause NESCAV syndrome (MIM#614255; OMIM). Both loss and gain of function mechanisms have been reported for variants causing spastic paraplegia 30 (MIM#610357, MIM#610357) and hereditary sensory and autonomic neuropathy type 2 (HSAN2; MIM#614213) (PMIDs: 31488895, 31455732). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. Genotype-phenotype correlation is currently unestablished. Missense variants tend to cluster within the kinesin motor domain and have been reported for both SPG30 and NESCAV syndrome. Only the correlation for HSAN2 (MIM#614213) is established with all patients except for one, carrying null variants outside the motor domain (PMID: 32737135). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated kinesin motor domain (DECIPHER). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Three alternative amino acid substitutions at the same position, p.(Arg13Leu), p.(Arg13Ser) and p.(Arg13His), have been classified as pathogenic or likely pathogenic by clinical laboratories in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by clinical laboratories in ClinVar, and has been observed in several individuals with spastic paraplegia including some de novo occurrences (PMIDs: 31813911, 32746806, 34487232). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Monoallelic KIF1A-related disorders: a multicenter cross sectional study and systematic literature review. | Vecchia SD | Journal of neurology | 2022 | PMID: 34487232 |
| Exome Sequencing in 200 Intellectual Disability/Autistic Patients: New Candidates and Atypical Presentations. | Valentino F | Brain sciences | 2021 | PMID: 34356170 |
| Heterozygous KIF1A variants underlie a wide spectrum of neurodevelopmental and neurodegenerative disorders. | Nicita F | Journal of medical genetics | 2021 | PMID: 32737135 |
| KIF1A-related autosomal dominant spastic paraplegias (SPG30) in Russian families. | Rudenskaya GE | BMC neurology | 2020 | PMID: 32746806 |
| A Novel de novo KIF1A Mutation in a Patient with Autism, Hyperactivity, Epilepsy, Sensory Disturbance, and Spastic Paraplegia. | Kurihara M | Internal medicine (Tokyo, Japan) | 2020 | PMID: 31813911 |
| KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia. | Pennings M | European journal of human genetics : EJHG | 2020 | PMID: 31488895 |
| Disease-associated mutations hyperactivate KIF1A motility and anterograde axonal transport of synaptic vesicle precursors. | Chiba K | Proceedings of the National Academy of Sciences of the United States of America | 2019 | PMID: 31455732 |
| A de novo dominant mutation in KIF1A associated with axonal neuropathy, spasticity and autism spectrum disorder. | Tomaselli PJ | Journal of the peripheral nervous system : JPNS | 2017 | PMID: 28834584 |
| Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
| https://deciphergenomics.org/patient/409447/genotype/221812 | - | - | - | - |
Text-mined citations for rs1064794935 ...
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 Nov 25, 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.