Submissions for variant NM_000549.5(TSHB):c.373del (p.Cys125fs)

gnomAD frequency: 0.00017  dbSNP: rs755485552

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000598622	SCV000709855	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect as c.373delT is shown to be biologically inactive (Medeiros-Neto et al., 1996); Frameshift variant predicted to result in protein truncation as the last 14 amino acids are replaced with 9 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 8636437, 22606512, 27362444, 31166470, 31703413, 31980526, 31384098, 15297803, 31589614)
Fulgent Genetics, Fulgent Genetics	RCV000503516	SCV002782397	pathogenic	Isolated thyroid-stimulating hormone deficiency	2022-05-31	criteria provided, single submitter	clinical testing
Invitae	RCV000598622	SCV003302470	pathogenic	not provided	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys125Valfs*10) in the TSHB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 14 amino acid(s) of the TSHB protein. This variant is present in population databases (rs755485552, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with clinical features of congenital hypothyroidism (PMID: 8636437, 15297803, 22606512, 27362444, 31166470). It has also been observed to segregate with disease in related individuals. This variant is also known as C105V or 313delT. ClinVar contains an entry for this variant (Variation ID: 437070). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects TSHB function (PMID: 8636437). For these reasons, this variant has been classified as Pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000503516	SCV003799170	pathogenic	Isolated thyroid-stimulating hormone deficiency	2022-11-15	criteria provided, single submitter	clinical testing	PS3, PM3_Strong
Revvity Omics, Revvity	RCV000503516	SCV003823735	pathogenic	Isolated thyroid-stimulating hormone deficiency	2022-11-15	criteria provided, single submitter	clinical testing
OMIM	RCV000503516	SCV000033770	pathogenic	Isolated thyroid-stimulating hormone deficiency	2002-10-01	no assertion criteria provided	literature only
Genetic Services Laboratory, University of Chicago	RCV002463363	SCV002064500	pathogenic	Pituitary hypothyroidism	2021-12-28	no assertion criteria provided	clinical testing	DNA sequence analysis of the TSHB gene demonstrated a single base pair deletion in exon 3, c.373del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 10 amino acids downstream of the change, p.Cys125Valfs*10. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated TSHB protein with potentially abnormal function. This sequence change has been described in the gnomAD database with a frequency of o.031% in the non-Finnish European subpopulation (dbSNP rs755485552). This pathogenic sequence change has previously been described in the homozygous and compound heterozygous state in multiple individuals with TSHB-related hypothyroidism (PMID: 31166470, 22606512, 31703413, 15297803, 27362444).