12-120993591-C-T

Position:

• chr12-120993591-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS4 PM5 PP1_Strong PP4_Moderate PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.598C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to tryptophan at codon 200 (p.(Arg200Trp)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.775, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.599G>A, p.(Arg200Gln), has been interpreted as pathogenic by the ClinGen MDEP, and p.Arg200Trp has a greater Grantham distance (PM5). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative autoantibodies) (PP4_Moderate; PMID:32238361). This variant was identified in at least ten unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 17440016, 9754819, 29927023, 32238361; internal lab contributors). Lastly, this variant segregated with diabetes, with five informative meioses in five families with MODY (PP1_Strong; internal lab contributors). In summary, c.598C>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 9/30/2021): PP1_Strong, PM2_Supporting, PP3, PS4, PP4_Moderate, PM5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA214311/MONDO:0015967/017

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 0.0640

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.598C>T	p.Arg200Trp	missense_variant	3/10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.598C>T	p.Arg200Trp	missense_variant	3/10		NP_001293108.2
HNF1A	NM_001406915.1	c.598C>T	p.Arg200Trp	missense_variant	3/9		NP_001393844.1
HNF1A	XM_024449168.2	c.598C>T	p.Arg200Trp	missense_variant	3/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.598C>T	p.Arg200Trp	missense_variant	3/10	1	NM_000545.8	ENSP00000257555	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461866 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000361 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2023	Published functional studies show possible interference with protein localization; however, proper localization does not appear to be entirely eliminated (Bjrkhaug et al., 2005); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28012402, 29927023, 33046911, 16274290, 12453420, 9754819, 22060211, 17440016, 24014008, 34789499, 28410371, 33852230, 34440499, 36208030, 36504295, 35796342, 12050210) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 30, 2022	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 200 of the HNF1A protein (p.Arg200Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with maturity-onset diabetes of the young (PMID: 9754819, 22060211, 33046911). ClinVar contains an entry for this variant (Variation ID: 36824). 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. This variant disrupts the p.Arg200 amino acid residue in HNF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15522234, 15841481, 16274290, 30663027; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 01, 2021	This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant associates with disease in multiple families. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments show this variant results in significant loss of nuclear localization of the HNF-1alpha protein (PMID: 16274290). The variant is located in a region that is considered important for protein function and/or structure. -

Maturity-onset diabetes of the young type 3 Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	-	- -
Pathogenic, criteria provided, single submitter	research	Geisinger Clinic, Geisinger Health System	Aug 02, 2022	PS4, PP1_strong, PM2, PM5, PP3, PP4 -

Maturity onset diabetes mellitus in young Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

May 14, 2021

Variant summary: HNF1A c.598C>T (p.Arg200Trp) results in a non-conservative amino acid change located in the Homeobox domain (IPR001356) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251336 control chromosomes (gnomAD). c.598C>T has been reported in the literature in multiple individuals affected with Maturity Onset Diabetes Of The Young 3 and has been documented to co-segregate with disease in affected families (e.g. Chevre_1998, Frayling_2001, Barrio_2002, Sahu_2007, Yorifuji_2012, Flannick_2013, Docena_2014, Bonnefond_2020, Ma_2020). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant causes a defect in nuclear import which is expected to lead to altered gene activity. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

Monogenic diabetes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Apr 10, 2022

The c.598C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to tryptophan at codon 200 (p.(Arg200Trp)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.775, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.599G>A, p.(Arg200Gln), has been interpreted as pathogenic by the ClinGen MDEP, and p.Arg200Trp has a greater Grantham distance (PM5). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative autoantibodies) (PP4_Moderate; PMID: 32238361). This variant was identified in at least ten unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 17440016, 9754819, 29927023, 32238361; internal lab contributors). Lastly, this variant segregated with diabetes, with five informative meioses in five families with MODY (PP1_Strong; internal lab contributors). In summary, c.598C>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 9/30/2021): PP1_Strong, PM2_Supporting, PP3, PS4, PP4_Moderate, PM5. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	.;D;D;D;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.23	N
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.3	D;.;.;D;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;.;.;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	.;.;.;.;D
Vest4		0.97
MVP		1.0
MPC		2.1
ClinPred		1.0	D
GERP RS		-0.34
gMVP		0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs193922598; hg19: chr12-121431394; COSMIC: COSV57460628; COSMIC: COSV57460628;