rs1322503729

Variant names:

• chr15-98939247-T-TGGCCGGAGAGATTGCAGAC
• rs1322503729
• NM_000875.5:c.3348_3366dupCGGAGAGATTGCAGACGGC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000875.5(IGF1R):​c.3348_3366dupCGGAGAGATTGCAGACGGC​(p.Met1123ArgfsTer14) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,910 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IGF1R NM_000875.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 10.0

Genes affected

IGF1R (HGNC:5465): (insulin like growth factor 1 receptor) This receptor binds insulin-like growth factor with a high affinity. It has tyrosine kinase activity. The insulin-like growth factor I receptor plays a critical role in transformation events. Cleavage of the precursor generates alpha and beta subunits. It is highly overexpressed in most malignant tissues where it functions as an anti-apoptotic agent by enhancing cell survival. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2014]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-98939247-T-TGGCCGGAGAGATTGCAGAC is Pathogenic according to our data. Variant chr15-98939247-T-TGGCCGGAGAGATTGCAGAC is described in ClinVar as [Pathogenic]. Clinvar id is 431965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.3348_3366dupCGGAGAGATTGCAGACGGC	p.Met1123ArgfsTer14	frameshift_variant	Exon 18 of 21	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.3348_3366dupCGGAGAGATTGCAGACGGC	p.Met1123ArgfsTer14	frameshift_variant	Exon 18 of 21		NM_000875.5	ENSP00000497069.1
IGF1R	ENST00000649865.1	c.3345_3363dupCGGAGAGATTGCAGACGGC	p.Met1122ArgfsTer14	frameshift_variant	Exon 18 of 21			ENSP00000496919.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461748 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727174

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: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74330

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Nov 29, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift 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; Published functional studies demonstrate nonsense-mediated mRNA decay and attenuated activation of the IGF1R pathway (Fang et al., 2009); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 19240156, 26578640, 26252249, 25866162, 25040157, 22180424, 21396585, 21204214, 14657428, 28395282) -

May 07, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Met1123Argfs*14) in the IGF1R gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IGF1R are known to be pathogenic (PMID: 14657428). This variant has been observed in individual(s) with autosomal dominant short stature (PMID: 19240156). ClinVar contains an entry for this variant (Variation ID: 431965). For these reasons, this variant has been classified as Pathogenic. -

Nov 16, 2020

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS3, PM2 -

Inborn genetic diseases Pathogenic:1

Feb 25, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The alteration results in a premature stop codon: _x000D_ _x000D_ The c.3348_3366dup19 (p.M1123Rfs*14) alteration, located in coding exon 18 of the IGF1R gene, consists of a duplication of the 19 nucleotides at position 3348 to 3366, causing a translational frameshift with a predicted alternate stop codon after 14 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The alteration has been observed in affected individuals: _x000D_ _x000D_ This alteration was identified in one family with short stature. The proband's height was -3.1 SDS, the mother's was -4.6 SDS, the sibling's was -1.94 SDS, and several other maternal family members were also reported to have short stature. Unlike other reported patients with IGF1R alterations, the proband was described to have normal circulating levels of GH binding protein, IGF-I, and IGF binding protein 2 (Fang, 2009). Functional analysis reveals a damaging effect of the amino acid alteration: _x000D_ _x000D_ Analyses of the primary dermal fibroblasts in a family with this alteration revealed a reduced amount of the normal IGF1R protein and diminished activation of the IGF1R pathway (Fang, 2009). Based on the available evidence, this alteration is classified as pathogenic. -

Growth delay due to insulin-like growth factor I resistance Pathogenic:1

Oct 29, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: IGF1R c.3348_3366dup19 (p.Met1123ArgfsX14) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251460 control chromosomes (gnomAD). c.3348_3366dup19 has been reported in the literature in at least an individual affected with IGF1R-related conditions (example: Klammt_2011). The following publication has been ascertained in the context of this evaluation (PMID: 21396585). ClinVar contains an entry for this variant (Variation ID: 431965). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1322503729; hg19: chr15-99482476;