chr14-81143715-G-A

Position:

chr14-81143715-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS1_ModeratePM1PP3_ModeratePP5

The NM_000369.5(TSHR):c.1657G>A(p.Ala553Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000589 in 1,613,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

TSHR
NM_000369.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8B:1

Conservation

PhyloP100: 10.0

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PS1

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

PM1

In a disulfide_bond (size 75) in uniprot entity TSHR_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_000369.5

PP3

MetaRNN computational evidence supports a deleterious effect, 0.87

PP5

Variant 14-81143715-G-A is Pathogenic according to our data. Variant chr14-81143715-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 6445.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_benign=1, Likely_pathogenic=2, Pathogenic=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSHR	NM_000369.5 linkuse as main transcript	c.1657G>A	p.Ala553Thr	missense_variant	10/10	ENST00000298171.7	NP_000360.2
LOC101928462	XR_001751022.2 linkuse as main transcript	n.487+21478C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSHR	ENST00000298171.7 linkuse as main transcript	c.1657G>A	p.Ala553Thr	missense_variant	10/10	1	NM_000369.5	ENSP00000298171	P1
	ENST00000646052.2 linkuse as main transcript	n.510+21478C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251360

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000622

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000688

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000692

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152022

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74236

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000464

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypothyroidism due to TSH receptor mutations

Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 15, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 16, 2024	Variant summary: TSHR c.1657G>A (p.Ala553Thr) results in a non-conservative amino acid change located in the GPCR, rhodopsin-like, 7TM domain (IPR017452) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251360 control chromosomes. c.1657G>A has been reported in the literature in multiple biallelic individuals affected with Hypothyroidism Due To TSH Receptor Mutations (e.g. Abramowicz_1997, Cangul_2010). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in reduced TSH-induced cyclic adenosine monophosphate (cAMP) signaling in COS-7 cells (Abramowicz_1997). The following publications have been ascertained in the context of this evaluation (PMID: 9185526, 20718767). ClinVar contains an entry for this variant (Variation ID: 6445). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The TSHR c.1657G>A (p.Ala553Thr) missense variant is described in five studies in which it is identified in seven patients with congenital hyopthyroidism including in a homozygous state in two pairs of consanguineous siblings and in a compound heterozygous state in two non-consanguineous siblings and an additional unrelated patient (Abramowicz et al. 1997; Park et al. 2004; Cangul et al. 2010; Cangul et al. 2012; van Tellingen et al. 2016). The variant was absent from 400 control alleles but is reported at a frequency of 0.00003 in the total population of the Exome Aggregation Consortium. Functional studies in COS-7 cells demonstrated that the p.Ala553Thr variant resulted in extremely low cell-surface expression of the receptor compared to wild type (Abramowicz et al. 1997). The Ala553 residue is highly conserved (Abramowicz et al. 1997; Cangul et al. 2010). Stability studies showed that the variant was expected to be significantly destabilizing for the protein (Cangul et al. 2010). Based on the collective evidence, the p.Ala553Thr variant is classified as likely pathogenic for congenital hypothyroidism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 07, 2016	- -

Familial gestational hyperthyroidism

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 23, 2024

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 08, 2021

The c.1657G>A (p.A553T) alteration is located in exon 10 (coding exon 10) of the TSHR gene. This alteration results from a G to A substitution at nucleotide position 1657, causing the alanine (A) at amino acid position 553 to be replaced by a threonine (T). Based on the available evidence, this variant is expected to be causative of congenital nongoitrous hypothyroidism (AR) when present along with a second pathogenic or likely pathogenic variant on the other allele; however, it is unlikely to be causative of nonautoimmune hyperthyroidism (AD). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (8/251360) total alleles studied. The highest observed frequency was 0.01% (2/30616) of South Asian alleles. This alteration has been detected in the homozygous state or compound heterozygous with a second TSHR variant in multiple unrelated individuals with congenital hypothyroidism (Abramowicz, 1997; Park, 2004; Cangul, 2010; van Tellingen, 2016). Heterozygous carriers of this variant have been reported with subclinical or mild hypothyroidism (Nicoletti, 2009; Abe, 2018). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

TSHR-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 02, 2024

The TSHR c.1657G>A variant is predicted to result in the amino acid substitution p.Ala553Thr. This variant has been reported in the monoallelic or bi-allelic state in individuals with Hypothyroidism (Abramowicz et al. 1997. PubMed ID: 9185526; Park et al. 2004. PubMed ID: 14725684; Abe et al. 2017. PubMed ID: 29092890). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as likely pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 26, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 553 of the TSHR protein (p.Ala553Thr). This variant is present in population databases (rs121908872, gnomAD 0.006%). This missense change has been observed in individual(s) with hypothyroidism (PMID: 9185526, 14725684, 20718767, 27255745, 29092890). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6445). 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 expected to disrupt TSHR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TSHR function (PMID: 9185526, 10560953). For these reasons, this variant has been classified as Pathogenic. -

Familial hyperthyroidism due to mutations in TSH receptor

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

.;D

M_CAP

Benign

0.067

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Uncertain

-0.024

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.5

D;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Vest4

0.93

MVP

0.97

MPC

0.64

ClinPred

0.94

GERP RS

5.5

gMVP

0.88

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

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