12-120994253-T-C

Position:

• chr12-120994253-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS2_Moderate PP3 PM2_Supporting PM1_Supporting PS4_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

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 Likely_pathogenic. Variant got 7 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.803T>C	p.Phe268Ser	missense_variant	4/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.803T>C	p.Phe268Ser	missense_variant	4/10
HNF1A	NM_001406915.1	c.803T>C	p.Phe268Ser	missense_variant	4/9
HNF1A	XM_024449168.2	c.803T>C	p.Phe268Ser	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.803T>C	p.Phe268Ser	missense_variant	4/10	1	NM_000545.8	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Dec 09, 2021

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 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 contributor). The MODY probability is unable to be calculated due to lack of clinical information (PMID: 27634015, PMID: 15305805). 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 (MODY probability calculator result >50% and negative genetic testing for HNF4A) (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. -

Maturity onset diabetes mellitus in young Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

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

Likely pathogenic, criteria provided, single submitter

clinical testing;curation

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

Aug 18, 2011

- -

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
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
MutationTaster	Benign	1.0	D;D;D;D;D
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

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: rs193922605; hg19: chr12-121432056;