ClinVar Genomic variation as it relates to human health
NM_001363.5(DKC1):c.1058C>T (p.Ala353Val)
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_001363.5(DKC1):c.1058C>T (p.Ala353Val)
Variation ID: 11587 Accession: VCV000011587.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq28 X: 154773152 (GRCh38) [ NCBI UCSC ] X: 154001427 (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 May 1, 2024 Aug 4, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001363.5:c.1058C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001354.1:p.Ala353Val missense NM_001142463.3:c.1058C>T NP_001135935.1:p.Ala353Val missense NM_001288747.2:c.1058C>T NP_001275676.1:p.Ala353Val missense NR_110021.2:n.1637C>T non-coding transcript variant NR_110022.2:n.1756C>T non-coding transcript variant NR_110023.2:n.1530C>T non-coding transcript variant NC_000023.11:g.154773152C>T NC_000023.10:g.154001427C>T NG_009780.1:g.15397C>T LRG_55:g.15397C>T LRG_55t1:c.1058C>T O60832:p.Ala353Val - Protein change
- A353V
- Other names
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- Canonical SPDI
- NC_000023.11:154773151:C:T
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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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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DKC1 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
460 | 672 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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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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Pathogenic (3) |
no assertion criteria provided
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Dec 1, 2009 | RCV000012343.28 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 4, 2023 | RCV000464438.10 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Aug 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Dyskeratosis congenita
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000553696.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
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) … (more)
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 DKC1 protein function. ClinVar contains an entry for this variant (Variation ID: 11587). This missense change has been observed in individual(s) with dyskeratosis congenita and it is known to be the most frequent cause of the disease (PMID: 10364516, 16332973, 19835419). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 353 of the DKC1 protein (p.Ala353Val). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects DKC1 function (PMID: 19391112, 19835419, 22058290, 25992652). (less)
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Pathogenic
(Nov 16, 2015)
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criteria provided, single submitter
Method: clinical testing
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Dyskeratosis congenita
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002710243.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.A353V pathogenic mutation (also known as c.1058C>T), located in coding exon 11 of the DKC1 gene, results from a C to T substitution at … (more)
The p.A353V pathogenic mutation (also known as c.1058C>T), located in coding exon 11 of the DKC1 gene, results from a C to T substitution at nucleotide position 1058. The alanine at codon 353 is replaced by valine, an amino acid with similar properties. This common recurring mutation has been observed in patients with dyskeratosis congenita or Hoyeraal-Hreidarsson syndrome from disparate geographical locations, and its occurrence has been reported to be de novo in multiple cases. (Knight SW et al, Am. J. Hum. Genet. 1999 Jul; 65(1):50-8; Viprakasit V et al, Haematologica 2001 Aug; 86(8):871-2; Ding YG et al, J. Invest. Dermatol. 2004 Sep; 123(3):470-3; Borggraefe I et al, J. Pediatr. Gastroenterol. Nutr. 2009 Sep; Grozdanov PN et al, Hum. Mol. Genet. 2009 Dec; 18(23):4546-51; Tamhankar PM et al, Indian J Pediatr 2010 Mar; 77(3):310-2; Lai W et al, J. Dermatol. Sci. 2011 Aug; 63(2):122-4; 49(3):359-63). Based on the available evidence, the p.A353V is classified as a pathogenic mutation. (less)
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Pathogenic
(Dec 01, 2009)
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no assertion criteria provided
Method: literature only
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DYSKERATOSIS CONGENITA, X-LINKED
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000032577.2
First in ClinVar: Apr 04, 2013 Last updated: Sep 21, 2013 |
Comment on evidence:
In a study that demonstrated missense mutations to be the predominant abnormality in the DKC1 gene leading to dyskeratosis congenita (305000), Knight et al. (1999) … (more)
In a study that demonstrated missense mutations to be the predominant abnormality in the DKC1 gene leading to dyskeratosis congenita (305000), Knight et al. (1999) found that the missense mutation ala353 to val (A353V) was present in 11 of 21 families in which they could demonstrate a mutation. The amino acid substitution was due to a 1058C-T transition in exon 11. It was found in both sporadic cases and multiplex families and in patients in the United Kingdom, Italy, France, United States, and Spain. In at least 5 instances, the mutation was de novo in the proband; in another case it was de novo in grandparents. Heiss et al. (2001) found the A353V mutation in another case of DKC. Yaghmai et al. (2000) reported a patient with striking features of Hoyeraal-Hreidarsson syndrome and DKC who carried the A353V mutation. Yaghmai et al. (2000) concluded that Hoyeraal-Hreidarsson syndrome may be a severe form of DKC in which affected individuals die before characteristic mucocutaneous features develop. Grozdanov et al. (2009) showed that the A353V mutation resulted in decreased binding affinity for SHQ1, likely resulting in loss of NAP57 due to degradation. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Dyskeratosis congenita, X-linked
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000055768.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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not provided
(-)
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no classification provided
Method: not provided
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Dyskeratosis congenita X-linked
Affected status: not provided
Allele origin:
germline
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UniProtKB/Swiss-Prot
Accession: SCV000090817.1
First in ClinVar: Oct 22, 2013 Last updated: Oct 22, 2013 |
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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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Dyskeratosis Congenita and Related Telomere Biology Disorders. | Adam MP | - | 2023 | PMID: 20301779 |
Impaired Telomere Maintenance and Decreased Canonical WNT Signaling but Normal Ribosome Biogenesis in Induced Pluripotent Stem Cells from X-Linked Dyskeratosis Congenita Patients. | Gu BW | PloS one | 2015 | PMID: 25992652 |
The accumulation and not the specific activity of telomerase ribonucleoprotein determines telomere maintenance deficiency in X-linked dyskeratosis congenita. | Zeng XL | Human molecular genetics | 2012 | PMID: 22058290 |
Identification of DKC1 gene mutation in an Indian patient. | Tamhankar PM | Indian journal of pediatrics | 2010 | PMID: 20091372 |
Single-molecule analysis of the human telomerase RNA.dyskerin interaction and the effect of dyskeratosis congenita mutations. | Ashbridge B | Biochemistry | 2009 | PMID: 19835419 |
Pathogenic NAP57 mutations decrease ribonucleoprotein assembly in dyskeratosis congenita. | Grozdanov PN | Human molecular genetics | 2009 | PMID: 19734544 |
Severe variant of x-linked dyskeratosis congenita (Hoyeraal-Hreidarsson Syndrome) causes significant enterocolitis in early infancy. | Borggraefe I | Journal of pediatric gastroenterology and nutrition | 2009 | PMID: 19633571 |
Variable expression of Dkc1 mutations in mice. | He J | Genesis (New York, N.Y. : 2000) | 2009 | PMID: 19391112 |
Mutations in dyskeratosis congenita: their impact on telomere length and the diversity of clinical presentation. | Vulliamy TJ | Blood | 2006 | PMID: 16332973 |
Identification of a novel mutation and a de novo mutation in DKC1 in two Chinese pedigrees with Dyskeratosis congenita. | Ding YG | The Journal of investigative dermatology | 2004 | PMID: 15304085 |
Recurrent A353V mutation in a Thai family with X-linked dyskeratosis congenita. | Viprakasit V | Haematologica | 2001 | PMID: 11522545 |
One novel and two recurrent missense DKC1 mutations in patients with dyskeratosis congenita (DKC). | Heiss NS | Genetic counseling (Geneva, Switzerland) | 2001 | PMID: 11491307 |
Overlap of dyskeratosis congenita with the Hoyeraal-Hreidarsson syndrome. | Yaghmai R | The Journal of pediatrics | 2000 | PMID: 10700698 |
X-linked dyskeratosis congenita is predominantly caused by missense mutations in the DKC1 gene. | Knight SW | American journal of human genetics | 1999 | PMID: 10364516 |
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Text-mined citations for rs121912288 ...
HelpRecord last updated May 27, 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.