Submissions for variant NM_000545.8(HNF1A):c.766T>A (p.Ser256Thr)

gnomAD frequency: 0.00001  dbSNP: rs781711191

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV002222063	SCV002499540	likely benign	Monogenic diabetes	2022-04-13	reviewed by expert panel	curation	The c.766T>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to threonine at codon 256 (p.Ser256Thr) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00003551, which is greater than the MDEP threshold for BS1 (greater than or equal to 0.000033) (BS1). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.782, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional studies demonstrated the p.Ser256Thr protein has DNA binding above 50% of wild type and normal nuclear localization and transactivation, indicating that this variant does not impact protein function (BS3_Supporting; PMID: 12574234). This variant was identified in three unrelated individuals 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 (PMID: 12574234, internal lab contributors). One of these individuals had a calculated MODY probability <50%, and the MODY probability could not be calculated in the other two due to limited clinical information, and PP4 could not be applied. In summary, c.766T>A 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 9/30/2021): PM1_Supporting, BS1, PP3, BS3_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001320339	SCV001511121	uncertain significance	not provided	2020-03-17	criteria provided, single submitter	clinical testing	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. This variant has been reported not to substantially affect HNF1A protein function (PMID: 12574234). This variant has been observed in individual(s) affected with clinical features of maturity-onset diabetes of the young (MODY) (PMID: 12574234). This variant is present in population databases (rs781711191, ExAC 0.002%). This sequence change replaces serine with threonine at codon 256 of the HNF1A protein (p.Ser256Thr). The serine residue is highly conserved and there is a small physicochemical difference between serine and threonine.