NM_000545.8:c.803T>C

Variant names:

• chr12-120994253-T-C
• rs193922605
• NM_000545.8:c.803T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1_Supporting PS4_Moderate PM2_Supporting PP3 PS2_Moderate

This summary comes from the ClinGen Evidence Repository: The c.803T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of phenylalanine to serine at codon 268 (p.(Phe268Ser)) of NM_000545.8. This variant is located within the DNA binding domain of HNF1A (codons 201-280), which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting), and is predicted to be deleterious by computational evidence, with a REVEL score of 0.986 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), but was identified in five unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID:27634015, PMID:15305805, ClinVar ID 36831, internal lab contributors). The MODY probability is unable to be calculated due to lack of clinical information (PMID:27634015, PMID:15305805, internal lab contributors). This variant was identified as a de novo occurrence with confirmed parental relationships in an individual with diabetes, but whose clinical picture is not highly specific for HNF1A-MODY (PS2_Moderate; internal lab contributor). Two other missense variants, c.802T>A p.(Phe268Ile)​ and c.802T>C p.(Phe268Leu) do not meet the criteria to be classified as likely pathogenic or pathogenic by the ClinGen MDEP without the addition of PM5 from this variant; therefore, PM5 will not be applied. In summary, the evidence supports the classification of c.803T>C as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.1, approved 8/18/2021): PS2_moderate, PS4_moderate, PP3, PM1_Supporting, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA214330/MONDO:0015967/017

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 7.60
• Publications: 2 publications found

Genes affected

HNF1A (HGNC:11621): (HNF1 homeobox A) The protein encoded by this gene is a transcription factor required for the expression of several liver-specific genes. The encoded protein functions as a homodimer and binds to the inverted palindrome 5'-GTTAATNATTAAC-3'. Defects in this gene are a cause of maturity onset diabetes of the young type 3 (MODY3) and also can result in the appearance of hepatic adenomas. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

HNF1A Gene-Disease associations (from GenCC):

• monogenic diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• type 1 diabetes mellitus 20

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• maturity-onset diabetes of the young type 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• hyperinsulinism due to HNF1A deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• nonpapillary renal cell carcinoma

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.803T>C	p.Phe268Ser	missense_variant	Exon 4 of 10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.803T>C	p.Phe268Ser	missense_variant	Exon 4 of 10		NP_001293108.2
HNF1A	NM_001406915.1	c.803T>C	p.Phe268Ser	missense_variant	Exon 4 of 9		NP_001393844.1
HNF1A	XM_024449168.2	c.803T>C	p.Phe268Ser	missense_variant	Exon 4 of 9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.803T>C	p.Phe268Ser	missense_variant	Exon 4 of 10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:1

Aug 05, 2025

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.803T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of phenylalanine to serine at codon 268 (p.(Phe268Ser)) of NM_000545.8. This variant is located within the DNA binding domain of HNF1A (codons 201-280), which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting), and is predicted to be deleterious by computational evidence, with a REVEL score of 0.986 (PP3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in four unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 27634015, PMID: 15305805, ClinVar ID 36831, internal lab contributors). This variant segregated with diabetes with one informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, PMID: 15305805). One of these individuals did have a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested, so PP4 cannot be applied (internal lab contributors). This variant was identified as a de novo occurrence with confirmed parental relationships in an individual with diabetes, but whose clinical picture is not highly specific for HNF1A-MODY (PS2_Moderate; internal lab contributor). Two other missense variants, c.802T>A p.(Phe268Ile) and c.802T>C p.(Phe268Leu) do not meet the criteria to be classified as likely pathogenic or pathogenic by the ClinGen MDEP without the addition of PM5 from this variant; therefore, PM5 will not be applied. In summary, the evidence supports the classification of c.803T>C as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0, approved 6/30/2025): PS2_Moderate, PS4_Moderate, PP3, PM1_Supporting, PM2_Supporting. -

Maturity onset diabetes mellitus in young Pathogenic:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. Sufficient evidence is found to confer the association of this particular variant rs193922605 with MODY3. -

Maturity-onset diabetes of the young type 3 Pathogenic:1

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	.;D;D;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.0	D
PhyloP100		7.6
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.4	D;.;D;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.99
MutPred		0.86		Gain of disorder (P = 0.0169);Gain of disorder (P = 0.0169);Gain of disorder (P = 0.0169);Gain of disorder (P = 0.0169);
MVP		1.0
MPC		2.8
ClinPred		1.0	D
GERP RS		4.8
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs193922605; hg19: chr12-121432056;