NM_003865.3(HESX1):c.475C>T (p.Arg159Trp) AND HESX1-Related Disorders

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Oct 14, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV004801040.1

Allele description [Variation Report for NM_003865.3(HESX1):c.475C>T (p.Arg159Trp)]

NM_003865.3(HESX1):c.475C>T (p.Arg159Trp)

Gene:

HESX1:HESX homeobox 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p14.3

Genomic location:

Preferred name:

NM_003865.3(HESX1):c.475C>T (p.Arg159Trp)

HGVS:

NC_000003.12:g.57198280G>A
NG_008242.1:g.6973C>T
NM_001376058.1:c.475C>T
NM_001376059.1:c.475C>T
NM_001376060.1:c.475C>T
NM_001376061.1:c.475C>T
NM_003865.3:c.475C>TMANE SELECT
NP_001362987.1:p.Arg159Trp
NP_001362988.1:p.Arg159Trp
NP_001362989.1:p.Arg159Trp
NP_001362990.1:p.Arg159Trp
NP_003856.1:p.Arg159Trp
NC_000003.11:g.57232308G>A
NM_003865.2:c.475C>T
NR_164757.1:n.968C>T

Protein change:

R159W

Links:

dbSNP: rs770886420

NCBI 1000 Genomes Browser:

rs770886420

Molecular consequence:

NM_001376058.1:c.475C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001376059.1:c.475C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001376060.1:c.475C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001376061.1:c.475C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_003865.3:c.475C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_164757.1:n.968C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: HESX1-Related Disorders
Identifiers:

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV005422249	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Oct 14, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31395954, 27000987, 28396770 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV005422249

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Oct 14, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

Citations

PubMed

Infant mortality: the contribution of genetic disorders.

Wojcik MH, Schwartz TS, Thiele KE, Paterson H, Stadelmaier R, Mullen TE, VanNoy GE, Genetti CA, Madden JA, Gubbels CS, Yu TW, Tan WH, Agrawal PB.

J Perinatol. 2019 Dec;39(12):1611-1619. doi: 10.1038/s41372-019-0451-5. Epub 2019 Aug 8.

PubMed [citation]

PMID:: 31395954
PMCID:: PMC6879816

HESX1 mutations in patients with congenital hypopituitarism: variable phenotypes with the same genotype.

Fang Q, Benedetti AF, Ma Q, Gregory L, Li JZ, Dattani M, Sadeghi-Nejad A, Arnhold IJ, Mendonca BB, Camper SA, Carvalho LR.

Clin Endocrinol (Oxf). 2016 Sep;85(3):408-14. doi: 10.1111/cen.13067. Epub 2016 Apr 28.

PubMed [citation]

PMID:: 27000987
PMCID:: PMC4988903

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005422249.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: HESX1 c.475C>T (p.Arg159Trp) results in a non-conservative amino acid change located in the Homeodomain (Homeodomain) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250890 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.475C>T has been reported in the literature in at least one compound heterozygous individual affected with Combined Pituitary Hormone Deficiency and pituitary aplasia (e.g., Fang_2016). The variant has also been reported in a heterozygous individual with Septooptic dysplasia, however a second HESX1 variant was not described and segregation of the variant with disease was not demonstrated (e.g., Wojcik_2019, Pozzi_2017). At least two publications report experimental evidence evaluating an impact on protein function, demonstrating that the variant results in altered localization, reduced protein expresssion, and altered or abolished repressor activity, possibly due to altered DNA binding abilities (e.g., Fang_2016, Pozzi_2017). The following publications have been ascertained in the context of this evaluation (PMID: 27000987, 28396770, 31395954). ClinVar contains an entry for this variant (Variation ID: 1206790). Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	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: May 16, 2025

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