rs121908865

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_ModeratePP5_Very_Strong

The NM_000369.5(TSHR):c.326G>A(p.Arg109Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,612,898 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

TSHR
NM_000369.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 5.78

Variant links:

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 links:

LOC101928462 (HGNC:):

LOC101928462 links:

ENSG00000284959 (HGNC:58172):

ENSG00000284959 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PS1

Transcript NM_000369.5 (TSHR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PP5

Variant 14-81087962-G-A is Pathogenic according to our data. Variant chr14-81087962-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-81087962-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSHR	NM_000369.5 link	c.326G>A	p.Arg109Gln	missense_variant	Exon 4 of 10	ENST00000298171.7	NP_000360.2	P16473A0A0A0MTJ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSHR	ENST00000298171.7 link	c.326G>A	p.Arg109Gln	missense_variant	Exon 4 of 10	1	NM_000369.5	ENSP00000298171.2		A0A0A0MTJ0

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251390

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1460674

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726760

show subpopulations

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:

0.00000810

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypothyroidism due to TSH receptor mutations

Pathogenic:2

Jun 18, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TSHR c.326G>A (p.Arg109Gln) results in a 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 2e-05 in 251390 control chromosomes. c.326G>A has been reported in the literature in the homozygous and compound heterozygous state in multiple individuals affected with Hypothyroidism Due To TSH Receptor Mutations (e.g. deFilippis_2017, Sigisawa_2018, Clifton-Bligh_1997, Watanabe_2021, Kara_2023). These data indicate that the variant is very likely to be associated with disease. In vitro studies in HEK293 and COS-7 cells show that this variant results in decreased enzyme activity and reduced binding affinity (e.g. Sugisawa_2018, Clifton-Bligh_1997). The following publications have been ascertained in the context of this evaluation (PMID: 9100579, 36913313, 30083029, 34234053, 28444304). ClinVar contains an entry for this variant (Variation ID: 6438). Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Pathogenic:1

Jun 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Aug 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects TSHR function (PMID: 9100579, 30083029). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSHR protein function. ClinVar contains an entry for this variant (Variation ID: 6438). This missense change has been observed in individual(s) with autosomal recessive hypothyroidism (PMID: 9100579, 27637299, 28444304, 30083029). 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 (rs121908865, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 109 of the TSHR protein (p.Arg109Gln). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.16

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

.;.;.;T;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.78

.;T;T;T;T

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.58

D;D;D;D;D

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.4

.;L;.;.;L

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.28

N;N;N;N;N

REVEL

Uncertain

0.55

Sift

Benign

0.77

T;T;T;T;T

Sift4G

Benign

0.76

T;T;T;T;T

Polyphen

1.0

.;D;.;.;.

Vest4

0.88

MVP

0.99

MPC

0.71

ClinPred

0.74

GERP RS

5.8

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.25

Position offset: -8

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over