Submissions for variant NM_000545.8(HNF1A):c.503G>A (p.Arg168His)

gnomAD frequency: 0.00001  dbSNP: rs377110124

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV004733217	SCV005367830	likely benign	Monogenic diabetes	2024-10-24	reviewed by expert panel	curation	The c.503G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to histidine at codon 168 (p.(Arg168His)) 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 is predicted to be deleterious by computational evidence, with a REVEL score of 0.886, which is greater than the MDEP VCEP threshold of 0.70 (PP3). The Grpmax filtering allele frequency of the c.503G>A variant in gnomAD v2.1.1 is 0.000017, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant was identified in a total of eight unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (internal lab contributors). However, in one case this variant was detected in trans with another variant in HNF1A that is classified as likely pathogenic by the ClinGen MDEP (BP2, internal lab contributors). In another case, this variant was detected in an individual with diabetes, who also harbored a whole gene deletion of HNF1B (BP5, internal lab contributors). Therefore, that leaves six individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes and this variant (PS4_Moderate, internal lab contributors). This variant was also identified in a normoglycemic individual >70 years old, and the expected penetrance for HNF1A-MODY is 95% by age 70 (BS2, internal lab contributors). Another missense variant at the same codon, c.503G>C p.Arg168Pro, has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.503G>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 2.1.0, approved 8/11/2023): BS2, BP2, BP5, PS4_Moderate, PP3, PM1_Supporting.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248895	SCV001422576	uncertain significance	Maturity-onset diabetes of the young type 3	2020-01-22	criteria provided, single submitter	curation	The p.Arg168His variant in HNF1A has not been previously reported in individuals with maturity-onset diabetes of the young and has been identified in 0.007% (2/30614) of South Asian chromosomes and 0.004% (5/113442) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs377110124). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg168His variant is uncertain. ACMG/AMP Criteria applied: BS1, PP3 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV005057152	SCV005719107	uncertain significance	not provided	2024-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 168 of the HNF1A protein (p.Arg168His). This variant is present in population databases (rs377110124, gnomAD 0.006%). This missense change has been observed in individual(s) with HNF1A-related conditions (PMID: 23348805). ClinVar contains an entry for this variant (Variation ID: 972756). 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 HNF1A 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.