Submissions for variant NM_000545.8(HNF1A):c.434C>T (p.Ser145Phe)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV002222038	SCV002499503	pathogenic	Monogenic diabetes	2022-04-08	reviewed by expert panel	curation	The c.434C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to phenylalanine at codon 145 (p.(Ser145Phe)) of NM_000545.8. This variant was identified in six unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 28701371, internal lab contributors). This variant segregated with diabetes, with 4 informative meioses in 2 families with MODY (PP1_Strong; PMID: 28701371, internal lab contributors). This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.989, which is greater than the MDEP threshold of 0.70 (PP3). Another missense variant, c.433T>C (p.(Ser145Pro)), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. This variant was identified in at least six individuals with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information, and PP4 cannot be applied (PMID:28701371, internal lab contributors). In summary, c.434C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved September 30, 2021): PP3, PM1, PM2_Supporting, PS4_Moderate, PP1_Strong.
Athena Diagnostics	RCV003482268	SCV000613614	pathogenic	not provided	2022-11-30	criteria provided, single submitter	clinical testing	This variant has been identified in multiple unrelated individuals with clinical features associated with this gene and appears to segregate with disease in at least one family (personal communication related to ClinVar ID 447489, lab code: 508240). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). The variant is located in a region that is considered important for protein function and/or structure. Computational tools predict that this variant is damaging.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002319512	SCV002604960	likely 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 rs1555211426 with MODY3.

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