NM_000545.8(HNF1A):c.511C>T (p.Arg171Ter) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jul 24, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000436030.12

Allele description [Variation Report for NM_000545.8(HNF1A):c.511C>T (p.Arg171Ter)]

NM_000545.8(HNF1A):c.511C>T (p.Arg171Ter)

Gene:

HNF1A:HNF1 homeobox A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q24.31

Genomic location:

Preferred name:

NM_000545.8(HNF1A):c.511C>T (p.Arg171Ter)

Other names:

NM_000545.8(HNF1A):c.511C>T; p.Arg171Ter

HGVS:

NC_000012.12:g.120989017C>T
NG_011731.2:g.15272C>T
NM_000545.6:c.511C>T
NM_000545.8:c.511C>TMANE SELECT
NM_001306179.2:c.511C>T
NP_000536.6:p.Arg171Ter
NP_001293108.2:p.Arg171Ter
LRG_522t1:c.511C>T
LRG_522:g.15272C>T
NC_000012.11:g.121426820C>T
NM_000545.5:c.511C>T
p.ARG171*

Protein change:

R171*

Links:

dbSNP: rs1057520291

NCBI 1000 Genomes Browser:

rs1057520291

Molecular consequence:

NM_000545.8:c.511C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001306179.2:c.511C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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commelinids acetyl-CoA carboxylase beta subunit (accD) gene, partial cds; chloro...
commelinids acetyl-CoA carboxylase beta subunit (accD) gene, partial cds; chloroplast.
PopSet: 1488098218

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B-cell receptor-associated protein 29 isoform b [Homo sapiens]
B-cell receptor-associated protein 29 isoform b [Homo sapiens]
gi|56549091|ref|NP_061332.2|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000513245	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Dec 6, 2022)	germline	clinical testing	Citation Link,
SCV000613619	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Nov 15, 2021)	unknown	clinical testing	PubMed (15) [See all records that cite these PMIDs] 31576961, 29439679, 28170077, 30121369, 34440499, 10102714, 10585442, 12107757, 12530534, 12574234, 15657605, 9097962, 9604876, 25525159, 26467025
SCV002241489	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 24, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9097962, 15928245, 18003757, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000513245

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Dec 6, 2022)

germline

clinical testing

Citation Link,

SCV000613619

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Pathogenic
(Nov 15, 2021)

unknown

clinical testing

PubMed (15)
[See all records that cite these PMIDs]

SCV002241489

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 24, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

MODY probability calculator for GCK and HNF1A screening in a multiethnic background population.

Tarantino RM, Abreu GM, Fonseca ACP, Kupfer R, Pereira MFC, Campos Júnior M, Zajdenverg L, Rodacki M.

Arch Endocrinol Metab. 2020 Feb;64(1):17-23. doi: 10.20945/2359-3997000000173. Epub 2019 Sep 30.

PubMed [citation]

PMID:: 31576961
PMCID:: PMC10522291

Comprehensive genomic analysis identifies pathogenic variants in maturity-onset diabetes of the young (MODY) patients in South India.

Mohan V, Radha V, Nguyen TT, Stawiski EW, Pahuja KB, Goldstein LD, Tom J, Anjana RM, Kong-Beltran M, Bhangale T, Jahnavi S, Chandni R, Gayathri V, George P, Zhang N, Murugan S, Phalke S, Chaudhuri S, Gupta R, Zhang J, Santhosh S, Stinson J, et al.

BMC Med Genet. 2018 Feb 13;19(1):22. doi: 10.1186/s12881-018-0528-6.

PubMed [citation]

PMID:: 29439679
PMCID:: PMC5811965

See all PubMed Citations (18)

Details of each submission

From GeneDx, SCV000513245.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Published functional studies demonstrate reduced DNA binding ability, transactivation potential and impaired mRNA stability (Thomas et al., 2002); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29439679, 9097962, 12574234, 27420379, 26641800, 12530534)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Athena Diagnostics, SCV000613619.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (15)

Description

This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies show that this variant results in reduced transactivation activity as well as loss of DNA binding activity (PMID: 10585442, 12107757, 12530534, 12574234). The variant is located in a region that is considered important for protein function and/or structure.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002241489.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 377965). This premature translational stop signal has been observed in individual(s) with maturity-onset diabetes of the young 3 (PMID: 9097962). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg171*) in the HNF1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HNF1A are known to be pathogenic (PMID: 15928245, 18003757).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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