NM_003235.5(TG):c.638+5G>A AND Iodotyrosyl coupling defect

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Aug 28, 2016
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000207481.7

Allele description [Variation Report for NM_003235.5(TG):c.638+5G>A]

NM_003235.5(TG):c.638+5G>A

Gene:

TG:thyroglobulin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

8q24.22

Genomic location:

Preferred name:

NM_003235.5(TG):c.638+5G>A

HGVS:

NC_000008.11:g.132873226G>A
NG_015832.1:g.11267G>A
NM_003235.5:c.638+5G>AMANE SELECT
NC_000008.10:g.133885471G>A
NM_003235.4:c.638+5G>A

Links:

dbSNP: rs774274702

NCBI 1000 Genomes Browser:

rs774274702

Molecular consequence:

NM_003235.5:c.638+5G>A - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:: Iodotyrosyl coupling defect (TDH3)
Synonyms:: HYPOTHYROIDISM, CONGENITAL, DUE TO DYSHORMONOGENESIS, 3; THYROID HORMONOGENESIS, GENETIC DEFECT IN, 3
Identifiers:: MONDO: MONDO:0010135; MedGen: C0342194; Orphanet: 95716; OMIM: 274700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000257396	Pediatric Genetics Division, Center for Pediatrics and Adolescent Medicine, University Medical Center Freiburg	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 1, 2013)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 26813946
SCV000471991	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Uncertain significance (Aug 28, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000257396

Pediatric Genetics Division, Center for Pediatrics and Adolescent Medicine, University Medical Center Freiburg

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 1, 2013)

germline

research

PubMed (2)
[See all records that cite these PMIDs]

SCV000471991

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Uncertain significance
(Aug 28, 2016)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
European Caucasoid	germline	no	2	not provided	not provided	2	yes	research
European Caucasoid	germline	yes	2	not provided	not provided	2	yes	research

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Against all odds: blended phenotypes of three single-gene defects.

Li Y, Salfelder A, Schwab KO, Grünert SC, Velten T, Lütjohann D, Villavicencio-Lorini P, Matysiak-Scholze U, Zabel B, Köttgen A, Lausch E.

Eur J Hum Genet. 2016 Aug;24(9):1274-9. doi: 10.1038/ejhg.2015.285. Epub 2016 Jan 27.

PubMed [citation]

PMID:: 26813946
PMCID:: PMC4989199

Details of each submission

From Pediatric Genetics Division, Center for Pediatrics and Adolescent Medicine, University Medical Center Freiburg, SCV000257396.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	European Caucasoid	1	not provided	yes	research	PubMed (2)
2	European Caucasoid	1	not provided	yes	research	PubMed (2)
3	European Caucasoid	1	not provided	yes	research	PubMed (2)
4	European Caucasoid	1	not provided	yes	research	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	discovery		1	not provided	not provided	See 1
2	germline	yes	1	not provided	discovery		1	not provided	not provided	See 2
3	germline	no	1	not provided	discovery		1	not provided	not provided	See 3
4	germline	no	1	not provided	discovery		1	not provided	not provided	See 4

Co-occurrences

#	Zygosity	Alleles	Number of Observations
1		NM_017662.4:c.2667+1G>A;NM_017662.4:c.2667+1G>A
2		NM_017662.4:c.2667+1G>A;NM_017662.4:c.2667+1G>A
3		NM_017662.4:c.2667+1G>A;NM_017662.4:c.2667+1G>A
4		NM_017662.4:c.2667+1G>A;NM_017662.4:c.2667+1G>A

From Illumina Laboratory Services, Illumina, SCV000471991.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The TG c.638+5G>A variant is a splice region variant that has been reported in one study in which it was found in a homozygous state in two Turkish siblings with thyroid dyshormonogenesis (Li et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00003 in the Total population of the Exome Aggregation Consortium. Functional studies using RT-PCR revealed the c.638+5G>A variant resulted in a loss of exon 5. However, not all transcripts with the c.638+5G>A variant were mis-spliced, as demonstrated by faint banding consistent with wild type. The evidence for this variant is limited. The c.638+5G>A variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for thyroid dyshormonogenesis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 4, 2024

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