rs193922587

Variant names:

• chr12-120999522-C-T
• rs193922587
• NM_000545.8:c.1663C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. BP5 PM2_Supporting BS2

This summary comes from the ClinGen Evidence Repository: The c.1663C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to phenylalanine at codon 555(p.(Leu555Phe)) of NM_000545.8. This variant has an allele frequency of 0.00001797 in Non-Finnish Europeans, below the MDEP threshold of 0.00002, and no copies in other subpopulations, in gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant was identified in the homozygous state in a 56 year old normoglycemic individual (BS2; PMID:22341299). Lastly, this variant was identified in a patient with an alternate molecular basis for disease (BP5; PMID:22341299). This variant was identified in one individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). This variant has a REVEL score of 0.5809, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function. In summary, c.1663C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): PM2_Supporting, BS2, BP5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA214281/MONDO:0015967/017

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Likely benign reviewed by expert panel P:1 U:2 B:2 O:1
• Conservation: PhyloP100: 0.975
• Publications: 4 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_benign. The variant received -4 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: 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.1663C>T	p.Leu555Phe	missense_variant	Exon 9 of 10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.1684C>T	p.Leu562Phe	missense_variant	Exon 9 of 10		NP_001293108.2
HNF1A	NM_001406915.1	c.1471C>T	p.Leu491Phe	missense_variant	Exon 8 of 9		NP_001393844.1
HNF1A	XM_024449168.2	c.1756C>T	p.Leu586Phe	missense_variant	Exon 8 of 9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.1663C>T	p.Leu555Phe	missense_variant	Exon 9 of 10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000806 AC: 2 AN: 248172 AF XY: 0.00000743

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461242 Hom.: 0 Cov.: 69 AF XY: 0.0000179 AC XY: 13 AN XY: 726932

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111906

Other (OTH) AF: 0.0000166 AC: 1 AN: 60364

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000235 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Uncertain:2 Benign:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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

- -

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Leu555Phe variant in HNF1A has been reported in 1 individual with maturity-onset diabetes of the young type 3 (PMID: 18003757) and has been identified in 0.001797% (2/111302) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922587). This variant has also been reported in ClinVar (VariationID: 36808) as likely pathogenic by Integrated Genetics. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. One affected individual with this variant have an alternative molecular basis for maturity-onset diabetes of the young, suggesting that this variant may not be pathogenic (PMID: 22341299). In summary, the clinical significance of the p.Leu555Phe variant is uncertain. ACMG/AMP Criteria applied: PM2, BP5 (Richards 2015). -

not provided Uncertain:1

Jul 14, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine with phenylalanine at codon 555 of the HNF1A protein (p.Leu555Phe). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs193922587, ExAC 0.002%). This missense change has been observed in individual(s) with maturity-onset diabetes of the young type 3 (PMID: 18003757). This missense change has been observed to be homozygous or hemizygous in an individual who did not have the expected clinical features for that genetic result (PMID: 22341299). ClinVar contains an entry for this variant (Variation ID: 36808). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Monogenic diabetes Benign:1

Dec 31, 2021

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.1663C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to phenylalanine at codon 555(p.(Leu555Phe)) of NM_000545.8. This variant has an allele frequency of 0.00001797 in Non- Finnish Europeans, below the MDEP threshold of 0.00002, and no copies in other subpopulations, in gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant was identified in the homozygous state in a 56 year old normoglycemic individual (BS2; PMID: 22341299). Lastly, this variant was identified in a patient with an alternate molecular basis for disease (BP5; PMID: 22341299). This variant was identified in one individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). This variant has a REVEL score of 0.5809, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function. In summary, c.1663C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): PM2_Supporting, BS2, BP5. -

HNF1A-related disorder Benign:1

Apr 29, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Maturity onset diabetes mellitus in young Other:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Uncertain risk allele

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. However, more evidence is required to confer the association of this particular variant rs193922587 with MODY3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	.;T;.;T;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.87	D;D;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.38	T;T;T;T;T
MetaSVM	Uncertain	-0.048	T
PhyloP100		0.97
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.93	N;.;.;N;N
REVEL	Uncertain	0.58
Sift	Uncertain	0.022	D;.;.;D;D
Sift4G	Benign	0.098	T;T;D;T;T
Polyphen		0.90	.;.;.;.;P
Vest4		0.37
MutPred		0.60		.;.;.;.;Loss of glycosylation at T564 (P = 0.1007);
MVP		0.99
MPC		0.39
ClinPred		0.77	D
GERP RS		3.6
gMVP		0.61
Mutation Taster		=3/97	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: rs193922587; hg19: chr12-121437325;