NM_006261.5(PROP1):c.425C>T (p.Ala142Val) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Apr 2, 2024
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:: RCV000177253.5

Allele description [Variation Report for NM_006261.5(PROP1):c.425C>T (p.Ala142Val)]

NM_006261.5(PROP1):c.425C>T (p.Ala142Val)

Gene:

PROP1:PROP paired-like homeobox 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q35.3

Genomic location:

Preferred name:

NM_006261.5(PROP1):c.425C>T (p.Ala142Val)

HGVS:

NC_000005.10:g.177992965G>A
NG_015889.1:g.8278C>T
NM_006261.5:c.425C>TMANE SELECT
NP_006252.3:p.Ala142Val
NP_006252.4:p.Ala142Val
NC_000005.9:g.177419966G>A
NM_006261.4:c.425C>T

Protein change:

A142V

Links:

dbSNP: rs143790367

NCBI 1000 Genomes Browser:

rs143790367

Molecular consequence:

NM_006261.5:c.425C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000229096	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Likely benign (Mar 27, 2017)	germline	clinical testing	Citation Link,
SCV005075826	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Apr 2, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 32870266, 38096238, 36407308 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000229096

Eurofins Ntd Llc (ga)

criteria provided, single submitter

(EGL Classification Definitions 2015)

Likely benign
(Mar 27, 2017)

germline

clinical testing

Citation Link,

SCV005075826

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Apr 2, 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	4	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Increased Burden of Rare Sequence Variants in GnRH-Associated Genes in Women With Hypothalamic Amenorrhea.

Delaney A, Burkholder AB, Lavender CA, Plummer L, Mericq V, Merino PM, Quinton R, Lewis KL, Meader BN, Albano A, Shaw ND, Welt CK, Martin KA, Seminara SB, Biesecker LG, Bailey-Wilson JE, Hall JE.

J Clin Endocrinol Metab. 2021 Mar 8;106(3):e1441-e1452. doi: 10.1210/clinem/dgaa609.

PubMed [citation]

PMID:: 32870266
PMCID:: PMC7947783

Exome sequencing in 16 patients with pituitary stalk interruption syndrome: A monocentric study.

Brauner R, Bignon-Topalovic J, Bashamboo A, McElreavey K.

PLoS One. 2023;18(12):e0292664. doi: 10.1371/journal.pone.0292664.

PubMed [citation]

PMID:: 38096238
PMCID:: PMC10721018

See all PubMed Citations (3)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000229096.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	not provided

#	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		4	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005075826.1

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

Description

Variant summary: PROP1 c.425C>T (p.Ala142Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 251096 control chromosomes (gnomAD). c.425C>T has been reported in the literature in individuals affected with Hypothalamic amenorrhoea or pituitary stalk interruption syndrome without strong evidence of causality (e.g. Delaney_2021, Dwyer_2022, Brauner_2023). These reports do not provide unequivocal conclusions about association of the variant with Combined Pituitary Hormone Deficiency. 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: 32870266, 36407308, 38096238). ClinVar contains an entry for this variant (Variation ID: 196432). Based on the evidence outlined above, the variant was classified as uncertain significance.

#	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: Sep 29, 2024

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