12-120993601-G-T

Variant names:

• chr12-120993601-G-T
• rs587780357
• NM_000545.8:c.608G>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000545.8(HNF1A):​c.608G>T​(p.Arg203Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R203S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 9.42
• Publications: 0 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: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000545.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-120993600-C-A is described in CliVar as Pathogenic. Clinvar id is 1676706.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 12-120993601-G-T is Pathogenic according to our data. Variant chr12-120993601-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1256577. Variant chr12-120993601-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1256577. Variant chr12-120993601-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1256577. Variant chr12-120993601-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1256577. Variant chr12-120993601-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1256577. Variant chr12-120993601-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1256577. Variant chr12-120993601-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1256577. Variant chr12-120993601-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1256577. Variant chr12-120993601-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1256577.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.608G>T	p.Arg203Leu	missense_variant	Exon 3 of 10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.608G>T	p.Arg203Leu	missense_variant	Exon 3 of 10		NP_001293108.2
HNF1A	NM_001406915.1	c.608G>T	p.Arg203Leu	missense_variant	Exon 3 of 9		NP_001393844.1
HNF1A	XM_024449168.2	c.608G>T	p.Arg203Leu	missense_variant	Exon 3 of 9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.608G>T	p.Arg203Leu	missense_variant	Exon 3 of 10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461880 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Feb 02, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg203 amino acid residue in HNF1A. Other variant(s) that disrupt this residue have been observed in individuals with HNF1A-related conditions (PMID: 21168233, 30293189, 31363388), which suggests that this may be a clinically significant amino acid residue. 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 expected to disrupt HNF1A protein function. ClinVar contains an entry for this variant (Variation ID: 1256577). This missense change has been observed in individual(s) with autosomal dominant maturity-onset diabetes of the young (Invitae). It has also been observed to segregate with disease in related individuals. This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 203 of the HNF1A protein (p.Arg203Leu). -

Sep 23, 2020

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Maturity onset diabetes mellitus in young Pathogenic:1

May 14, 2025

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HNF1A c.608G>T (p.Arg203Leu) results in a non-conservative amino acid change located in the Nuclear localization signal (amino acids 197-205; UniProt), and also affects the overlapping Homeodomain (amino acids 199-282; IPR001356) altering a residue which is involved directly in DNA recognition; thus the substitution of this amino acid (Arg203) might have dual potential consequences on hepatocyte nuclear factor 1-alpha (HNF1A) function (PMID 15726414). Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant was absent in 251318 control chromosomes (gnomAD). c.608G>T has been observed in individuals affected with Maturity Onset Diabetes Of The Young 3 (Labcorp [formerly Invitae] internal data). These data indicate that the variant may be associated with disease. Different variants affecting the same codon have been classified as pathogenic by our lab (i.e. c.607C>T, p.Arg203Cys and c.608G>A, p.Arg203His), supporting the critical relevance of codon 203 to HNF1A protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 1256577). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	.;D;T;D;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
PhyloP100		9.4
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.9	D;.;.;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;.;.;D;D
Sift4G	Uncertain	0.039	D;D;D;D;D
Polyphen		0.014	.;.;.;.;B
Vest4		0.94
MutPred		0.82		Loss of disorder (P = 0.0432);Loss of disorder (P = 0.0432);Loss of disorder (P = 0.0432);Loss of disorder (P = 0.0432);Loss of disorder (P = 0.0432);
MVP		1.0
MPC		1.2
ClinPred		0.99	D
GERP RS		4.5
gMVP		0.99
Mutation Taster		=5/95	disease causing

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: rs587780357; hg19: chr12-121431404; COSMIC: COSV57460658;