Submissions for variant NM_000545.8(HNF1A):c.871C>T (p.Pro291Ser)

gnomAD frequency: 0.00006  dbSNP: rs151256267

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV001814997	SCV002059997	likely benign	Monogenic diabetes	2022-01-03	reviewed by expert panel	curation	The c.871C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to serine at codon 291 (p.(Pro291Ser)) of NM_000545.8. • This variant has been observed in unknown phase with the variant c.494G>A, p.Trp165Ter (internal lab contributors), which is classified as pathogenic by the ClinGen MDEP (BP2). Functional studies demonstrated the p.Pro291Ser protein has abnormal nuclear localization above 75% of wildtype, indicating that this variant does not impact protein function (PMID: 32910913) (BS3_Supporting). Lastly, this variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00001163, which is greater than or equal to the MDEP threshold for BS1 (≥0.000033) (BS1). In summary, c.871C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved ***): BP2, BS3_Supporting, BS1
Athena Diagnostics	RCV000516527	SCV000613636	benign	not specified	2017-04-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000863499	SCV001004173	benign	not provided	2023-11-20	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001115117	SCV001273062	likely benign	Maturity-onset diabetes of the young type 3	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003900072	SCV004714084	likely benign	HNF1A-related disorder	2021-02-19	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000516527	SCV004848501	benign	not specified	2020-11-06	criteria provided, single submitter	clinical testing	The p.Pro291Ser variant in HNF1A is classified as benign because it has been identified in 0.5% (54/9958) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org) and several species (including at least 4 mammals, namely the bat, bushbaby, squirel, mole) carry a Serine (Ser) at this position despite high nearby amino acid conservation. Computational prediction tools further suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. ACMG/AMP Criteria applied: BS1, BP4_Strong.
Ambry Genetics	RCV004023509	SCV005036151	likely benign	Maturity onset diabetes mellitus in young	2023-12-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.