14-81092547-C-G

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PM1 PM5 PP2 PP5_Very_Strong BP4

The NM_000369.5(TSHR):​c.484C>G​(p.Pro162Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000214 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P162S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: TSHR NM_000369.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 4.64
• Publications: 33 publications found

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]

TSHR Gene-Disease associations (from GenCC):

• familial gestational hyperthyroidism

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• hypothyroidism due to TSH receptor mutations

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• familial hyperthyroidism due to mutations in TSH receptor

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• athyreosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• thyroid hypoplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TSHR-AS1 (HGNC:58172):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_000369.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-81092547-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 623326.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 43 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 0.33445 (below the threshold of 3.09). Trascript score misZ: 1.3127 (below the threshold of 3.09). GenCC associations: The gene is linked to hypothyroidism due to TSH receptor mutations, athyreosis, familial hyperthyroidism due to mutations in TSH receptor, familial gestational hyperthyroidism, thyroid hypoplasia.
• PP5: Variant 14-81092547-C-G is Pathogenic according to our data. Variant chr14-81092547-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 6435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.39315754). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSHR	NM_000369.5	c.484C>G	p.Pro162Ala	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>G	p.Pro162Ala	missense_variant	Exon 6 of 10	1	NM_000369.5	ENSP00000298171.2

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152060 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000143 AC: 36 AN: 251382 AF XY: 0.000162

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000220 AC: 321 AN: 1461810 Hom.: 0 Cov.: 31 AF XY: 0.000230 AC XY: 167 AN XY: 727210

African (AFR) AF: 0.0000598 AC: 2 AN: 33468

American (AMR) AF: 0.000112 AC: 5 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.000267 AC: 297 AN: 1111966

Other (OTH) AF: 0.0000994 AC: 6 AN: 60392

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152178 Hom.: 0 Cov.: 33 AF XY: 0.000202 AC XY: 15 AN XY: 74410

African (AFR) AF: 0.0000482 AC: 2 AN: 41504

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68010

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000164 Hom.: 0

Bravo AF: 0.000140

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000173 AC: 21

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000415

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypothyroidism due to TSH receptor mutations Pathogenic:4

Apr 20, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TSHR c.484C>G (p.Pro162Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251382 control chromosomes (gnomAD). c.484C>G has been reported in the literature in at least two homozygous individuals affected with Hypothyroidism Due To TSH Receptor Mutations (e.g. Tonacchera_1996, Camilot_2005), and in multiple other homozygous, compound heterozygous, and heterozygous individuals with resistance to TSH and subclinical hypothyroidism, presenting as abnormally high TSH levels but with normal thyroid hormone levels (e.g. Sunthornthepvarakul_1995, Tonacchera_1996, De Roux_1996, Camilot_2005, Bas_2012, Tenenbaum-Rakover_2015, de Filippis_2017, Makretskaya_2018). Publications reporting experimental evidence evaluating an impact on protein function found that the variant is associated with an approximately 2-fold reduction in cell surface expression and results in a protein capable of reaching a maximal activity level similar to WT in vitro, but with a reduced sensitivity to TSH (e.g. Sunthornthepvarakul_1995, Costagliola_1999, Sriphrapradang_2011). These data indicate that the variant is likely a hypomorphic allele which manifests as elevated TSH in most cases, but has reduced penetrance and/or a milder phenotype with regards to whether individuals present clinically with hypothyroidism or have subclinical hypothyroidism. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=2)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Jun 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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>G (p.Pro162Ala) variant found in homozygous state in two unrelated families from our cohort. Variant has been reported in ClinVar as Likely pathogenic (★★) and several publications also have reported the variant in CH cases (PubMed:10560953, PubMed:16060907, PubMed:12050212, PubMed:30240412) (PP5). The variant is located in a mutational hot spot without benign variation (PM1). The variant allele was found at extremely low frequency in population databases, with no homozygous occurrence (PM2). Another missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before (PM5). Patient’s phenotype or family history is highly specific for congenital hypothyroidism due to TSHR mutations (PP4). This is a missense variant in a gene in which missense variants are a common mechanism of disease (PP2). The variant c.484C>G is Pathogenic according to the ACMG guideline criteria. -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS3_Supporting+PM3_VeryStrong+PP4 -

not provided Pathogenic:4

Feb 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 162 of the TSHR protein (p.Pro162Ala). This variant is present in population databases (rs121908863, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive TSHR-related conditions (PMID: 7528344, 8954020, 16060907, 28444304). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6435). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects TSHR function (PMID: 7528344, 10560953). For these reasons, this variant has been classified as Pathogenic. -

Jan 17, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported heterozygous in individuals with subclinical hypothyroidism with variable expressivity (PMID: 17697008, 16060907); Published functional studies demonstrate a damaging effect on normal TSHR function (PMID: 10560953, 7528344); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 7528344, 20718767, 34426522, 31589614, 22995991, 26990548, 23329763, 16060907, 12050212, 28444304, 17456567, 31287502, 30240412, 25557138, 34200080, 23154162, 34308104, 34919466, 15531543, 26229975, 28404951, 28719003, 26934580, 26659599, 31855179, 28007035, 26986070, 29691392, 27915290, 26147798, 21490078, 17697008, 26740555, 30665703, 11549705, 8954020, 10560953) -

Jun 14, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial gestational hyperthyroidism Pathogenic:1

Aug 09, 2022

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial hyperthyroidism due to mutations in TSH receptor;C1863959:Familial gestational hyperthyroidism;C3493776:Hypothyroidism due to TSH receptor mutations Pathogenic:1

Jun 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Uncertain	0.12
CADD	Benign	23
DANN	Benign	0.85
DEOGEN2	Uncertain	0.59	.;.;.;D;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	.;D;D;D;D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.39	T;T;T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.8	.;L;.;.;L
PhyloP100		4.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.75	N;N;N;N;N
REVEL	Uncertain	0.46
Sift	Benign	0.066	T;T;T;T;T
Sift4G	Benign	0.49	T;T;T;T;T
Polyphen		0.25	.;B;.;.;.
Vest4		0.65
MVP		0.99
MPC		0.32
ClinPred		0.057	T
GERP RS		5.3
gMVP		0.72
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs121908863; hg19: chr14-81558891;