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NM_000208.4(INSR):c.3164C>T (p.Ala1055Val) AND not provided

Germline classification:
Likely pathogenic (2 submissions)
Last evaluated:
Aug 28, 2019
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV001811619.15

Allele description

NM_000208.4(INSR):c.3164C>T (p.Ala1055Val)

Gene:
INSR:insulin receptor [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
19p13.2
Genomic location:
Preferred name:
NM_000208.4(INSR):c.3164C>T (p.Ala1055Val)
HGVS:
  • NC_000019.10:g.7125377G>A
  • NG_008852.2:g.173624C>T
  • NM_000208.4:c.3164C>TMANE SELECT
  • NM_001079817.3:c.3128C>T
  • NP_000199.2:p.Ala1055Val
  • NP_001073285.1:p.Ala1043Val
  • NC_000019.9:g.7125388G>A
Protein change:
A1043V
Links:
dbSNP: rs1599874183
NCBI 1000 Genomes Browser:
rs1599874183
Molecular consequence:
  • NM_000208.4:c.3164C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079817.3:c.3128C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001160653ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)		Likely pathogenic
(Aug 28, 2019) 		germlineclinical testing

Citation Link,

SCV003839621Genetic Services Laboratory, University of Chicago
no assertion criteria provided
Likely pathogenic
(Feb 18, 2022) 		germlineclinical testing

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001160653.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The INSR c.3164C>T; p.Ala1055Val variant, also known in alternative nomenclature as p.Ala1028Val, is reported in the literature in several individuals affected with type A insulin resistance and Rabson-Mendenhall syndrome (Jiang 2011, Rique 2000). Parental testing of one affected individuals with this variant indicated it occurred de novo (Jiang 2011), while the other affected individual had relatives found to carry this variant who had high serum insulin levels (Rique 2000). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Functional studies in cultured cells suggest that the p.Ala1055Val protein is poorly processed to its mature form and exhibits decreased signaling activity (Jiang 2011). Based on available information, this variant is considered to be likely pathogenic. References: Jiang S et al. Mendenhall syndrome - phenotypic heterogeneity of insulin receptor gene mutations. Endocr J. 2011;58(11):931-40. Rique S et al. Identification of three novel mutations in the insulin receptor gene in type A insulin resistant patients. Clin Genet. 2000 Jan;57(1):67-9.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Genetic Services Laboratory, University of Chicago, SCV003839621.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

DNA sequence analysis of the INSR gene demonstrated a sequence change, c.3164C>T, in exon 17 that results in an amino acid change, p.Ala1055Val. The p.Ala1055Val change affects a highly conserved amino acid residue located in a domain of the INSR protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ala1055Val substitution. Experimental studies have demonstrated that this sequence change impacts the function of the INSR protein (PMID: 21869538). This sequence change has been described in the literature in the heterozygous and compound heterozygous state in individuals with INSR-related disorders (https://abstracts.eurospe.org/hrp/0089/hrp0089p2-p351, PMID: 10733238, 21869538, 34789499). This sequence change has not been described in population databases such as ExAC and gnomAD. Collectively, these evidences indicate this sequence change is likely pathogenic, however, clinical correlation is recommended.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 16, 2024