chr12-120993613-G-A

Position:

• chr12-120993613-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1_Supporting PS4_Moderate PP1_Strong PP4_Moderate PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.620G>A variant in the HNF1 Homeobox A gene, HNF1A, causes an amino acid change of glycine to aspartic acid at codon 207 (p.(Gly207Asp)) of NM_000545.8. 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 response to low dose sulfonylurea) (PP4_Moderate). This variant was identified in six unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate). Furthermore, this variant segregated with diabetes, with 10 informative meioses, in one family with MODY (PP1_Strong). The glycine at the 207 codon position is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.937, which is greater than the MDEP VCEP threshold of 0.70 (PP3). In summary, c.620G>A 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, PM1_Supporting, PM2_Supporting, PS4_Moderate, PP4_Moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA386964424/MONDO:0015967/017

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4 U:1
• Conservation: PhyloP100: 9.42

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 11 ACMG points.

• 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.
• 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.620G>A	p.Gly207Asp	missense_variant	3/10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.620G>A	p.Gly207Asp	missense_variant	3/10		NP_001293108.2
HNF1A	NM_001406915.1	c.620G>A	p.Gly207Asp	missense_variant	3/9		NP_001393844.1
HNF1A	XM_024449168.2	c.620G>A	p.Gly207Asp	missense_variant	3/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.620G>A	p.Gly207Asp	missense_variant	3/10	1	NM_000545.8	ENSP00000257555	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461876 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Maturity onset diabetes mellitus in young Pathogenic:2

Likely risk allele, 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. However, more evidence is required to confer the association of this particular variant rs1555211922 with MODY3. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 02, 2023	Variant summary: HNF1A c.620G>A (p.Gly207Asp) results in a non-conservative amino acid change to a highly conserved residue 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 251266 control chromosomes. c.620G>A has been reported in the literature in multiple individuals affected with Maturity Onset Diabetes Of The Young (Ellard_2006, Frayling_2001, Kyithat_2011, Shepherd_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. An expert panel (ClinGen Monogenic Diabetes Variant Curation Expert Panel) (evaluation after 2014) cites the variant as pathogenic in ClinVar. Another ClinVar submitter (evaluation after 2014) cites it as uncertain significance. 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

Jun 10, 2022

The c.620G>A variant in the HNF1 Homeobox A gene, HNF1A, causes an amino acid change of glycine to aspartic acid at codon 207 (p.(Gly207Asp)) of NM_000545.8. 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 response to low dose sulfonylurea) (PP4_Moderate). This variant was identified in six unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate). Furthermore, this variant segregated with diabetes, with 10 informative meioses, in one family with MODY (PP1_Strong). The glycine at the 207 codon position is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.937, which is greater than the MDEP VCEP threshold of 0.70 (PP3). In summary, c.620G>A 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, PM1_Supporting, PM2_Supporting, PS4_Moderate, PP4_Moderate, PP3. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 13, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16496320, 26110317, 22808921, 21683639, 20393147, 16917892, 24069322, 23803251, 12453420, 18003757, 35328643, 32395877, 31517624, 32910913, 35673428, 30229274, 23674172, 26479152) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 09, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	.;D;D;D;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.2	D;.;.;D;D
REVEL	Pathogenic	0.94
Sift	Benign	0.043	D;.;.;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		1.0	.;.;.;.;D
Vest4		0.87
MutPred		0.59		Loss of MoRF binding (P = 0.0892);Loss of MoRF binding (P = 0.0892);Loss of MoRF binding (P = 0.0892);Loss of MoRF binding (P = 0.0892);Loss of MoRF binding (P = 0.0892);
MVP		0.95
MPC		2.4
ClinPred		1.0	D
GERP RS		4.5
gMVP		0.98

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: rs1555211922; hg19: chr12-121431416; COSMIC: COSV57462070; COSMIC: COSV57462070;