rs760874290

Positions:

• chr14-81091070-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_000369.5(TSHR):​c.394G>C​(p.Gly132Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000808 in 1,609,618 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: TSHR NM_000369.5 missense, splice_region
• Scores: Splicing: ADA: 0.9796
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1 B:2
• Conservation: PhyloP100: 5.93

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSHR	NM_000369.5	c.394G>C	p.Gly132Arg	missense_variant, splice_region_variant	5/10	ENST00000298171.7
LOC101928462	XR_001751022.2	n.881+2512C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSHR	ENST00000298171.7	c.394G>C	p.Gly132Arg	missense_variant, splice_region_variant	5/10	1	NM_000369.5	P1
	ENST00000646052.2	n.904+2512C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000330 AC: 5 AN: 151670 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000402 AC: 10 AN: 248890 Hom.: 0 AF XY: 0.0000445 AC XY: 6 AN XY: 134716

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000549 AC: 8 AN: 1457948 Hom.: 0 Cov.: 30 AF XY: 0.00000689 AC XY: 5 AN XY: 725494

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000330 AC: 5 AN: 151670 Hom.: 0 Cov.: 33 AF XY: 0.0000270 AC XY: 2 AN XY: 74018

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000963

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000378

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial gestational hyperthyroidism Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 26, 2024

- -

TSHR-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

-

This variant has been previously reported as a de novo compound heterozygous and homozygous change in patients with congenital nongoitrous hypothyroidism-1 (CHNG1) who exhibited increased levels of plasma TSH and low levels of thyroid hormone in infancy (PMID: 21707688, 19158199). Functional studies showed that the presence of the (p.Gly132Arg) variant resulted in reduced binding activity and impaired TSH-induced cAMP production (26% of wild type) without any significant reduction in expression level (PMID: 19158199). The c.394G>C (p.Gly132Arg) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.004% (12/280224) and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, the c.394G>C (p.Gly132Arg) variant is classified as Likely Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 13, 2016

The G132R variant in the TSHR gene has been reported previously in association with congenital hypothyroidism (Lee et al., 2011; Narumi et al., 2011). And, functional characterization of the G132R variant indicates a disruption in receptor function (Narumi et al., 2009). The G132R variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project; however, data from ethnically-matched control individuals were not available to assess for a population-specific benign variant. The G132R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The G132R variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -

Hypothyroidism due to TSH receptor mutations Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

The TSHR c.394G>C (p.Gly132Arg) missense variant has been reported in at least three studies in which it is found in a total of six patients with congenital hypothyroidism, including in one in a homozygous state, in two in a compound heterozygous state, in two in a heterozygous state, and in a heterozygous state in one patient who also carried a missense variant in another congenital hypothyroidism-associated gene (Narumi et al. 2009; Lee et al. 2011; Jin et al. 2014). The majority of these studies, however, did not screen for all the known causal genes. The p.Gly132Arg variant was absent from 100 controls, but is reported at a frequency of 0.00047 in the East Asian population of the Exome Aggregation Consortium. Functional studies in COS-7 cells showed that the p.Gly132Arg variant protein was expressed at a level comparable to that of the wild type protein but displayed severely reduced binding activity and impaired TSH-induced cAMP production (26% of wild type) (Narumi et al. 2009). The evidence for this variant is limited. The p.Gly132Arg variant is therefore classified as likley pathogenic for congenital hypothyroidism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

Familial hyperthyroidism due to mutations in TSH receptor Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	27
DANN	Pathogenic	1.0
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.096	D
MetaRNN	Uncertain	0.74	D;D;D;D;D
MetaSVM	Uncertain	-0.27	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.9	N;D;N;D;D
REVEL	Pathogenic	0.70
Sift	Benign	0.082	T;D;T;D;D
Sift4G	Benign	0.098	T;T;T;T;T
Polyphen		0.95	.;P;.;.;.
Vest4		0.91
MutPred		0.74		Gain of MoRF binding (P = 0.0221);Gain of MoRF binding (P = 0.0221);Gain of MoRF binding (P = 0.0221);Gain of MoRF binding (P = 0.0221);Gain of MoRF binding (P = 0.0221);
MVP		0.98
MPC		0.44
ClinPred		0.42	T
GERP RS		5.8
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.77
SpliceAI score (max)		0.050		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: rs760874290; hg19: chr14-81557414;