ClinVar Miner

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

gnomAD frequency: 0.00193  dbSNP: rs143790367
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000177253 SCV000229096 likely benign not specified 2017-03-27 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000274096 SCV000456754 uncertain significance Pituitary hormone deficiency, combined, 2 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp RCV000896336 SCV001040422 benign not provided 2024-01-31 criteria provided, single submitter clinical testing
GeneDx RCV000896336 SCV003798904 uncertain significance not provided 2023-02-01 criteria provided, single submitter clinical testing Identified as heterozygous in two unrelated patients in published literature presenting with either amenorrhea or pituitary stalk interruption syndrome (Delaney et al., 2020; Hietamki et al., 2022); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 36034425, 32870266, 35875813)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000177253 SCV005075826 uncertain significance not specified 2024-04-02 criteria provided, single submitter clinical testing 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.
Natera, Inc. RCV000274096 SCV001457801 likely benign Pituitary hormone deficiency, combined, 2 2020-01-05 no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000896336 SCV001799124 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000896336 SCV001925179 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000896336 SCV001964310 likely benign not provided no assertion criteria provided clinical testing
Yale Center for Mendelian Genomics, Yale University RCV001849329 SCV002106773 uncertain significance Amenorrhea 2021-03-08 no assertion criteria provided literature only

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