14-80955802-G-C

Variant names:

• chr14-80955802-G-C
• rs121908869
• NM_000369.5:c.122G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP2 PP3 PP5

The NM_000369.5(TSHR):​c.122G>C​(p.Cys41Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000347 in 1,614,100 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).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: TSHR NM_000369.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 5.58
• Publications: 22 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]

CEP128 (HGNC:20359): (centrosomal protein 128) Involved in protein localization. Located in centriole and spindle pole. Part of centriolar subdistal appendage. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.801
• PP5: Variant 14-80955802-G-C is Pathogenic according to our data. Variant chr14-80955802-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 6442.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000369.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSHR	NM_000369.5	MANE Select	c.122G>C	p.Cys41Ser	missense	Exon 1 of 10	NP_000360.2
	TSHR	NM_001142626.3		c.122G>C	p.Cys41Ser	missense	Exon 1 of 9	NP_001136098.1
	TSHR	NM_001018036.3		c.122G>C	p.Cys41Ser	missense	Exon 1 of 9	NP_001018046.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSHR	ENST00000298171.7	TSL:1 MANE Select	c.122G>C	p.Cys41Ser	missense	Exon 1 of 10	ENSP00000298171.2
	TSHR	ENST00000554435.1	TSL:1	c.122G>C	p.Cys41Ser	missense	Exon 1 of 9	ENSP00000450549.1
	TSHR	ENST00000342443.10	TSL:1	c.122G>C	p.Cys41Ser	missense	Exon 1 of 9	ENSP00000340113.6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152232 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: 0.00

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

GnomAD2 exomes AF: 0.0000400 AC: 10 AN: 249792 AF XY: 0.0000370

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000892

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000376 AC: 55 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.0000426 AC XY: 31 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000486 AC: 54 AN: 1112010

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74370

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000455 Hom.: 0

Bravo AF: 0.0000113

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Epilepsy;C0424605:Developmental delay;C1846135:autistic features Pathogenic:1

Jul 04, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hypothyroidism due to TSH receptor mutations Pathogenic:1

Jun 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:1

Jul 16, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect with loss of function of the receptor and a partial dominate negative effect (PMID: 11278376, 16135555); Identified as a single heterozygous variant in patients with hypothyroidism in published literature (PMID: 12050212, 28561265, 33124651); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 1584215, 21745101, 11278376, 16135555, 8954020, 12050212, 28444304, 37047169, 36125728, 29625052, 31541602, 34200080, 33124651, 25978107, 16117192, 28561265, 36451132)

Familial hyperthyroidism due to mutations in TSH receptor Pathogenic:1

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic.

not specified Uncertain:1

Jun 12, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TSHR c.122G>C (p.Cys41Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 249792 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TSHR causing Hypothyroidism Due To TSH Receptor Mutations, allowing no conclusion about variant significance. c.122G>C has been reported in the literature in individuals affected with Hypothyroidism Due To TSH Receptor Mutations (deRoux_1996, Acar_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34780050, 19417038, 16117192, 8954020). ClinVar contains an entry for this variant (Variation ID: 6442). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	-0.024	T
MutationAssessor	Benign	1.0	L
PhyloP100		5.6
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.74
Sift	Benign	0.26	T
Sift4G	Benign	0.099	T
Polyphen		1.0	D
Vest4		0.93
MutPred		0.72		Gain of catalytic residue at R38 (P = 0.009)
MVP		0.99
MPC		0.73
ClinPred		0.76	D
GERP RS		5.2
PromoterAI		0.098	Neutral
gMVP		0.95
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121908869; hg19: chr14-81422146;