NM_000207.3(INS):c.71C>A (p.Ala24Asp) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 2, 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:: RCV001818156.6

Allele description [Variation Report for NM_000207.3(INS):c.71C>A (p.Ala24Asp)]

NM_000207.3(INS):c.71C>A (p.Ala24Asp)

Genes:

INS-IGF2:INS-IGF2 readthrough [Gene - HGNC]
INS:insulin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p15.5

Genomic location:

Preferred name:

NM_000207.3(INS):c.71C>A (p.Ala24Asp)

HGVS:

NC_000011.10:g.2160901G>T
NG_007114.1:g.5294C>A
NG_050578.1:g.5309C>A
NM_000207.3:c.71C>AMANE SELECT
NM_001042376.3:c.71C>A
NM_001185097.2:c.71C>A
NM_001185098.2:c.71C>A
NM_001291897.2:c.71C>A
NP_000198.1:p.Ala24Asp
NP_001035835.1:p.Ala24Asp
NP_001172026.1:p.Ala24Asp
NP_001172027.1:p.Ala24Asp
NP_001278826.1:p.Ala24Asp
NC_000011.9:g.2182131G>T
NC_000011.9:g.2182131G>T
NM_000207.2:c.71C>A
NR_003512.4:n.130C>A
P01308:p.Ala24Asp

Protein change:

A24D; ALA24ASP

Links:

UniProtKB: P01308#VAR_063723; UniProtKB/Swiss-Prot: VAR_063723; OMIM: 176730.0012; dbSNP: rs80356663

NCBI 1000 Genomes Browser:

rs80356663

Molecular consequence:

NM_000207.3:c.71C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001042376.3:c.71C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001185097.2:c.71C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001185098.2:c.71C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001291897.2:c.71C>A - missense variant - [Sequence Ontology: SO:0001583]
NR_003512.4:n.130C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002067500	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 19, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004294056	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 2, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17855560, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002067500

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jun 19, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004294056

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 2, 2023)

germline

clinical testing

PubMed (2)
[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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Insulin gene mutations as a cause of permanent neonatal diabetes.

Støy J, Edghill EL, Flanagan SE, Ye H, Paz VP, Pluzhnikov A, Below JE, Hayes MG, Cox NJ, Lipkind GM, Lipton RB, Greeley SA, Patch AM, Ellard S, Steiner DF, Hattersley AT, Philipson LH, Bell GI; Neonatal Diabetes International Collaborative Group..

Proc Natl Acad Sci U S A. 2007 Sep 18;104(38):15040-4. Epub 2007 Sep 12.

PubMed [citation]

PMID:: 17855560
PMCID:: PMC1986609

See all PubMed Citations (3)

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV002067500.1

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

Description

DNA sequence analysis of the INS gene demonstrated a sequence change, c.71C>A, in exon 2 that results in an amino acid change, p.Ala24Asp. This sequence change is absent from large population databases such as ExAC and gnomAD (dbSNP rs80356663). The p.Ala24Asp change affects a highly conserved amino acid residue located in region of insulin protein (signal peptide cleavage site) that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ala24Asp substitution. This particular amino acid change has been described in multiple patients with permanent neonatal diabetes (PMIDs: 17855560, 18162506, and 18171712). Functional studies have shown that p.Ala24Asp mutant results in aberrant processing of proinsulin to insulin and retention of proinsulin in the endoplasmic reticulum (PMIDs: 19952343, 22357960). Pathogenic variants in INS cause permanent neonatal diabetes [OMIM# 606176]. Most cases of INS-associated neonatal diabetes are inherited in an autosomal dominant manner; however autosomal recessive cases have also been reported.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV004294056.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 24 of the INS protein (p.Ala24Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant neonatal diabetes (PMID: 17855560). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13388). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.

#	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: Sep 29, 2024

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