Submissions for variant NM_000545.8(HNF1A):c.1663C>T (p.Leu555Phe)

gnomAD frequency: 0.00001  dbSNP: rs193922587

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV001810405	SCV002059995	likely benign	Monogenic diabetes	2021-12-31	reviewed by expert panel	curation	The c.1663C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to phenylalanine at codon 555(p.(Leu555Phe)) of NM_000545.8. This variant has an allele frequency of 0.00001797 in Non- Finnish Europeans, below the MDEP threshold of 0.00002, and no copies in other subpopulations, in gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant was identified in the homozygous state in a 56 year old normoglycemic individual (BS2; PMID: 22341299). Lastly, this variant was identified in a patient with an alternate molecular basis for disease (BP5; PMID: 22341299). This variant was identified in one individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). This variant has a REVEL score of 0.5809, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function. In summary, c.1663C>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 1.1, approved 6/4/2021): PM2_Supporting, BS2, BP5.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030488	SCV000053158	likely pathogenic	Maturity-onset diabetes of the young type 3	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Likely pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000030488	SCV001422864	uncertain significance	Maturity-onset diabetes of the young type 3	2020-01-22	criteria provided, single submitter	curation	The p.Leu555Phe variant in HNF1A has been reported in 1 individual with maturity-onset diabetes of the young type 3 (PMID: 18003757) and has been identified in 0.001797% (2/111302) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922587). This variant has also been reported in ClinVar (VariationID: 36808) as likely pathogenic by Integrated Genetics. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. One affected individual with this variant have an alternative molecular basis for maturity-onset diabetes of the young, suggesting that this variant may not be pathogenic (PMID: 22341299). In summary, the clinical significance of the p.Leu555Phe variant is uncertain. ACMG/AMP Criteria applied: PM2, BP5 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852602	SCV002183908	uncertain significance	not provided	2021-07-14	criteria provided, single submitter	clinical testing	This sequence change replaces leucine with phenylalanine at codon 555 of the HNF1A protein (p.Leu555Phe). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs193922587, ExAC 0.002%). This missense change has been observed in individual(s) with maturity-onset diabetes of the young type 3 (PMID: 18003757). This missense change has been observed to be homozygous or hemizygous in an individual who did not have the expected clinical features for that genetic result (PMID: 22341299). ClinVar contains an entry for this variant (Variation ID: 36808). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002463618	SCV002605158	uncertain risk allele	Maturity onset diabetes mellitus in young		criteria provided, single submitter	research	Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. However, more evidence is required to confer the association of this particular variant rs193922587 with MODY3.
PreventionGenetics, part of Exact Sciences	RCV004752727	SCV005364657	likely benign	HNF1A-related disorder	2024-04-29	no assertion criteria provided	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).