VCV000639452.42 - ClinVar

NM_198253.3(TERT):c.999CTC[1] (p.Ser335del)

Germline

Classification

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.

(4)

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.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_198253.3(TERT):c.999CTC[1] (p.Ser335del)

Variation ID: 639452 Accession: VCV000639452.42

Type and length

Microsatellite, 3 bp

Location

Cytogenetic: 5p15.33 5: 1293882-1293884 (GRCh38) [ NCBI UCSC ] 5: 1293997-1293999 (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	Aug 14, 2019	Jun 17, 2024	Nov 10, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_198253.3:c.1002_1004del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_198253.3:c.1002_1004delCTC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_198253.3:c.999CTC[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_937983.2:p.Ser335del	inframe deletion
NM_001193376.3:c.999CTC[1]	NP_001180305.1:p.Ser335del	inframe deletion
NM_198253.2:c.1002_1004delCTC		inframe deletion
NR_149162.3:n.1078CTC[1]		non-coding transcript variant
NR_149163.3:n.1078CTC[1]		non-coding transcript variant
NC_000005.10:g.1293882GAG[1]
NC_000005.9:g.1293997GAG[1]
NG_009265.1:g.6161CTC[1]
LRG_343:g.6161CTC[1]
LRG_343t1:c.1002_1004del

... more HGVS ... less HGVS

Protein change

S335del

Other names

p.Ser335del

Canonical SPDI

NC_000005.10:1293881:GAGGAG:GAG

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

dbSNP: rs1170942980 VarSome

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
Gene	OMIM	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.
TERT		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2985	3428

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.
Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1	Likely pathogenic (1)	criteria provided, single submitter	May 19, 2022	RCV002332584.9
Pulmonary fibrosis	Likely risk allele (1)	no assertion criteria provided	Jun 9, 2022	RCV002509537.8
Dyskeratosis congenita, autosomal dominant 2 Idiopathic Pulmonary Fibrosis	Uncertain significance (1)	criteria provided, single submitter	Sep 12, 2023	RCV002535868.10
Dyskeratosis congenita, autosomal dominant 2	Uncertain significance (1)	criteria provided, single submitter	Nov 10, 2023	RCV004569502.1

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.
Likely pathogenic (May 19, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 Affected status: yes Allele origin: germline	Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center Accession: SCV002520365.1 First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 Comment: p.Ser335del	Number of individuals with the variant: 1 Age: 70-79 years Sex: female Ethnicity/Population group: American Admixed/Latino Geographic origin: United States
Uncertain significance (Sep 12, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Dyskeratosis congenita, autosomal dominant 2 Idiopathic Pulmonary Fibrosis 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: SCV000931528.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 26329388‚ 28102861 Comment: This variant, c.1002_1004del, results in the deletion of 1 amino acid(s) of the TERT protein (p.Ser335del), but otherwise preserves the integrity of the reading frame. … (more) This variant, c.1002_1004del, results in the deletion of 1 amino acid(s) of the TERT protein (p.Ser335del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 639452). This variant has been observed in individual(s) with clinical features of dyskeratosis congenita (PMID: 26329388, 28102861). (less)
Uncertain significance (Nov 10, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dyskeratosis congenita, autosomal dominant 2 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV005052995.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Likely risk allele (Jun 09, 2022)	no assertion criteria provided Method: research	Pulmonary fibrosis Affected status: yes Allele origin: germline	Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center Accession: SCV002547346.1 First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023	Comment: Leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted

Comment:

This variant, c.1002_1004del, results in the deletion of 1 amino acid(s) of the TERT protein (p.Ser335del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 639452). This variant has been observed in individual(s) with clinical features of dyskeratosis congenita (PMID: 26329388, 28102861).

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical utility of next-generation sequencing for inherited bone marrow failure syndromes.	Muramatsu H	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 28102861
Clinical and genetic features of dyskeratosis congenita, cryptic dyskeratosis congenita, and Hoyeraal-Hreidarsson syndrome in Japan.	Yamaguchi H	International journal of hematology	2015	PMID: 26329388

Text-mined citations for rs1170942980 ...

These 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 10, 2024

ClinVar Genomic variation as it relates to human health

NM_198253.3(TERT):c.999CTC[1] (p.Ser335del)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1170942980 ...