14-81092547-C-T

Variant names:

• chr14-81092547-C-T
• rs121908863
• NM_000369.5:c.484C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_000369.5(TSHR):​c.484C>T​(p.Pro162Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,810 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P162A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TSHR NM_000369.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 4.64

Genes affected

TSHR (HGNC:12373): (thyroid stimulating hormone receptor) The protein encoded by this gene is a membrane protein and a major controller of thyroid cell metabolism. The encoded protein is a receptor for thyrothropin and thyrostimulin, and its activity is mediated by adenylate cyclase. Defects in this gene are a cause of several types of hyperthyroidism. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

LOC101928462 (HGNC:):

ENSG00000284959 (HGNC:58172):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSHR	NM_000369.5	c.484C>T	p.Pro162Ser	missense_variant	Exon 6 of 10	ENST00000298171.7	NP_000360.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSHR	ENST00000298171.7	c.484C>T	p.Pro162Ser	missense_variant	Exon 6 of 10	1	NM_000369.5	ENSP00000298171.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461810 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypothyroidism due to TSH receptor mutations Pathogenic:1 Uncertain:1

Dec 30, 2017

Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Apr 15, 2025

Constantin Polychronakos Laboratory, The Research Institute of the McGill University Health Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NM_000369.5(TSHR):c.484C>T(p.Pro162Ser) variant was found in a proband with thyroid hypoplasia born to consanguineous parents (first cousins). The variant allele was found at a frequency of 0.00000342 in the GnomAD database, with no homozygous occurrence (PM2). Variant has been reported in ClinVar as Uncertain significance (★). It also has been reported previously to cause congenital hypothyroidism in literature (PubMed: 30240412). Another variant affecting the same amino acid position but resulting in a different missense (i.e. P162A) has been classified as Likely pathogenic (PM5). Patient’s phenotype or family history is highly specific for congenital hypothyroidism due to TSHR mutations (PP4). The variant detected in a homozygous state in affected cases in congenital hypothyroidism due to TSHR mutation with a possibility of recessive inheritance (PM3). c.484C>T is located in a mutational hot spot without benign variation (PM1). According to the ACMG guideline, this variant is classified as a Pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	.;.;.;D;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	.;D;D;D;D
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.64	D;D;D;D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.94	.;L;.;.;L
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.2	N;N;N;N;N
REVEL	Uncertain	0.44
Sift	Uncertain	0.017	D;D;D;D;D
Sift4G	Benign	0.40	T;D;T;D;D
Polyphen		0.97	.;D;.;.;.
Vest4		0.64
MutPred		0.54		Gain of catalytic residue at E157 (P = 0.001);Gain of catalytic residue at E157 (P = 0.001);Gain of catalytic residue at E157 (P = 0.001);Gain of catalytic residue at E157 (P = 0.001);Gain of catalytic residue at E157 (P = 0.001);
MVP		0.99
MPC		0.40
ClinPred		0.94	D
GERP RS		5.3
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121908863; hg19: chr14-81558891;