Submissions for variant NM_000458.4(HNF1B):c.1117G>A (p.Ala373Thr)

gnomAD frequency: 0.00001  dbSNP: rs759270956

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000732396	SCV000860353	uncertain significance	not provided	2018-03-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000732396	SCV002056033	uncertain significance	not provided	2021-12-17	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002464303	SCV002745703	uncertain risk allele	Maturity onset diabetes mellitus in young		criteria provided, single submitter	research	HNF1B gene mutations are associated with early onset diabetes and pancreatic atrophy. It is also associated with multiple renal manifestations including renal cysts, Tubulointerstitial disease, glomerulocystic disease, renal hypoplasia, hypomagnesemia. However no sufficient evidence is found to ascertain the role of this particular variant rs759270956, yet.
Fulgent Genetics, Fulgent Genetics	RCV002485915	SCV002793062	uncertain significance	Renal cysts and diabetes syndrome; Type 2 diabetes mellitus; Nonpapillary renal cell carcinoma	2022-05-06	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000732396	SCV004229333	uncertain significance	not provided	2023-01-13	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000732396	SCV004397904	uncertain significance	not provided	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 373 of the HNF1B protein (p.Ala373Thr). This variant is present in population databases (rs759270956, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with HNF1B-related conditions. ClinVar contains an entry for this variant (Variation ID: 596527). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HNF1B protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Neuberg Centre For Genomic Medicine, NCGM	RCV004546560	SCV005042828	uncertain significance	Renal cysts and diabetes syndrome		criteria provided, single submitter	clinical testing	The missense c.1117G>Ap.Ala373Thr variant in HNF1B gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The variant is reported with an allele frequency of 0.001% in the gnomAD exomes database and is novel not in any individuals in 1000 Genomes database. This variant has been reported to the ClinVar database as Uncertain significance multiple submission. The amino acid change p.Ala373Thr in HNF1B is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ala at position 373 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance VUS.