NM_000369.5(TSHR):c.1963_1964del (p.Thr655fs) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jun 12, 2024
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:: RCV001570778.5

Allele description [Variation Report for NM_000369.5(TSHR):c.1963_1964del (p.Thr655fs)]

NM_000369.5(TSHR):c.1963_1964del (p.Thr655fs)

Genes:

TSHR-AS1:TSHR antisense RNA 1 [Gene - HGNC]
TSHR:thyroid stimulating hormone receptor [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

14q31.1

Genomic location:

Preferred name:

NM_000369.5(TSHR):c.1963_1964del (p.Thr655fs)

HGVS:

NC_000014.9:g.81144021_81144022del
NG_009206.1:g.193497_193498del
NM_000369.5:c.1963_1964delMANE SELECT
NP_000360.2:p.Thr655fs
LRG_523t1:c.1963_1964del
LRG_523:g.193497_193498del
NC_000014.8:g.81610364_81610365del
NC_000014.8:g.81610365_81610366del
NM_000369.2:c.1963_1964del
NM_000369.2:c.1963_1964delAC

Protein change:

T655fs

Links:

OMIM: 603372.0031; dbSNP: rs761918916

NCBI 1000 Genomes Browser:

rs761918916

Molecular consequence:

NM_000369.5:c.1963_1964del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001795126	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jun 12, 2024)	germline	clinical testing	Citation Link,
SCV004297145	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Aug 7, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9589691, 12050212, 22049173, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001795126

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jun 12, 2024)

germline

clinical testing

Citation Link,

SCV004297145

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Aug 7, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Apparent congenital athyreosis contrasting with normal plasma thyroglobulin levels and associated with inactivating mutations in the thyrotropin receptor gene: are athyreosis and ectopic thyroid distinct entities?

Gagné N, Parma J, Deal C, Vassart G, Van Vliet G.

J Clin Endocrinol Metab. 1998 May;83(5):1771-5.

PubMed [citation]

PMID:: 9589691

Germline mutations of TSH receptor gene as cause of nonautoimmune subclinical hypothyroidism.

Alberti L, Proverbio MC, Costagliola S, Romoli R, Boldrighini B, Vigone MC, Weber G, Chiumello G, Beck-Peccoz P, Persani L.

J Clin Endocrinol Metab. 2002 Jun;87(6):2549-55.

PubMed [citation]

PMID:: 12050212

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV001795126.2

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

Description

Identified with a second variant in the TSHR gene in a patient with severe congenital hypothyroidism; please note that this variant is referred to as delAC655 using alternate nomenclature (PMID: 9589691); Identified in the heterozygous state in a patient with nonautoimmune subclinical hypothyroidism; please note that this variant is referred to as T655del using alternate nomenclature (PMID: 12050212); Frameshift variant predicted to result in abnormal protein length as the last 110 amino acids are replaced with 1 different amino acid, and other similar variants have been reported in HGMD; Functional studies demonstrate that this variant, described using alternate nomenclature T655del, leads to a loss of function (PMID: 12050212); This variant is associated with the following publications: (PMID: 14604307, 34200080, 12050212, 34426522, 35177841, 22049173, 9589691)

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004297145.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this premature translational stop signal affects TSHR function (PMID: 12050212). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 1204435). This variant is also known as del AC 655; T655X; T655delta-TSHR. This premature translational stop signal has been observed in individual(s) with hypothyroidism (PMID: 9589691, 12050212, 22049173). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs761918916, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Thr655Cysfs*2) in the TSHR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 110 amino acid(s) of the TSHR protein.

#	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: Jan 25, 2025

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