NM_198253.3(TERT):c.1317GGA[2] (p.Glu441del) AND Dyskeratosis congenita

Germline classification:: Likely benign (2 submissions)
Last evaluated:: May 18, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001261857.10

Allele description [Variation Report for NM_198253.3(TERT):c.1317GGA[2] (p.Glu441del)]

NM_198253.3(TERT):c.1317GGA[2] (p.Glu441del)

Gene:

TERT:telomerase reverse transcriptase [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

5p15.33

Genomic location:

Preferred name:

NM_198253.3(TERT):c.1317GGA[2] (p.Glu441del)

HGVS:

NC_000005.10:g.1293563CTC[2]
NC_000005.9:g.1293676_1293678del
NG_009265.1:g.6479GGA[2]
NM_001193376.3:c.1317GGA[2]
NM_198253.3:c.1317GGA[2]MANE SELECT
NP_001180305.1:p.Glu441del
NP_937983.2:p.Glu441del
NP_937983.2:p.Glu441del
LRG_343:g.6479GGA[2]
NC_000005.9:g.1293676_1293678del
NC_000005.9:g.1293676_1293678delTCC
NC_000005.9:g.1293678CTC[2]
NM_198253.2:c.1323_1325delGGA
NM_198253.3:c.1317_1319GGA[2]MANE SELECT
NR_149162.3:n.1396GGA[2]
NR_149163.3:n.1396GGA[2]

Protein change:

E441del

Links:

dbSNP: rs377639087

NCBI 1000 Genomes Browser:

rs377639087

Molecular consequence:

NM_001193376.3:c.1317GGA[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_198253.3:c.1317GGA[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NR_149162.3:n.1396GGA[2] - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_149163.3:n.1396GGA[2] - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Dyskeratosis congenita
Identifiers:: MONDO: MONDO:0015780; MedGen: C0265965; OMIM: PS127550

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001439199	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	criteria provided, single submitter (St. Jude Assertion Criteria 2020)	Likely benign (Sep 10, 2020)	germline	clinical testing	Citation Link,
SCV002533101	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Likely benign (May 18, 2021)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001439199

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

criteria provided, single submitter

(St. Jude Assertion Criteria 2020)

Likely benign
(Sep 10, 2020)

germline

clinical testing

Citation Link,

SCV002533101

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Likely benign
(May 18, 2021)

germline

curation

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Details of each submission

From St. Jude Molecular Pathology, St. Jude Children's Research Hospital, SCV001439199.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The p.Glu441del frameshift variant has a frequency of 0.001719 (311 of 180,940 alleles) in gnomAD v2.1.1 with a maximal allele frequency of 0.003621 (261 of 72,072) in the European non-Finnish subpopulation (http://gnomad.broadinstitute.org). Pathogenic variants in the TERT gene predispose individuals to dyskeratosis congenita (DKC). While the exact prevalence of DKC is unknown, it is estimated to occur in approximately 1 in 1 million people. Therefore, the population frequency is not consistent with disease (BS1). This variant has been reported as heterozygous in an individual with aplastic anemia (PMID: 19674077) and as homozygous in an individual with acute myeloid leukemia (PMID: 19147845). The variant represents an in-frame deletion of 1 glutamic acid residue in a repeat of 3 glutamic acid residues (BP3). Results of telomerase activity assays have been conflicting. In several reports, the E441del variant has similar activity to the wild-type allele (PMID: 15814878, 23901009), however another report demonstrated approximately 40% of functional activity as compared to the wild-type allele (PMID: 19147845). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1, BP3.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Sema4, Sema4, SCV002533101.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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