Submissions for variant NM_022168.4(IFIH1):c.1641+1G>C

gnomAD frequency: 0.00728  dbSNP: rs35337543

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000245122	SCV000314018	benign	not specified		criteria provided, single submitter	clinical testing
Invitae	RCV000545421	SCV000655023	benign	Singleton-Merten syndrome 1; Aicardi-Goutieres syndrome 7	2024-01-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000584843	SCV000693003	benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	IFIH1: BS1, BS2
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000545421	SCV000898745	uncertain significance	Singleton-Merten syndrome 1; Aicardi-Goutieres syndrome 7	2021-06-14	criteria provided, single submitter	clinical testing	IFIH1 NM_022168.3 intron 8 c.1641+1G>C: This variant has not been reported in the literature in association with traditional Mendelian disease, but has been reported as heterozygous in 3 healthy children who were hospitalized due to viral infection (Asgari 2017 PMID:28716935). This variant is present in 1% (745/67940) of European alleles, including 4 homozygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/19-19193983-A-T?dataset=gnomad_r3. This variant is present in ClinVar (Variation ID:261563) with at least 2 labs classifying this variant as Benign. Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant alters the consensus splice sequence (+/- 1,2) which is predicted to result in an absent or abnormal protein. However, there is limited evidence for this gene and to support loss of function (LOF) as a known disease mechanism. In vitro functional studies suggest that this variant will impact the protein by causing an in-frame loss of 39 amino acids and the skipping of exon 8; thus potentially disrupting signaling function, enzymatic activity and protein stability (Asgari 2017 PMID:28716935). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224242	SCV003920049	uncertain significance	Singleton-Merten syndrome 1; Aicardi-Goutieres syndrome 7; Immunodeficiency 95	2022-10-13	criteria provided, single submitter	clinical testing	IFIH1 NM_022168.3 exon 8 c.1641+1G>C: This variant has not been reported in the literature in association with traditional Mendelian disease, but has been reported as heterozygous in 3 healthy children who were hospitalized due to viral infection (Asgari 2017 PMID:28716935). This variant is present in 1% (1362/125804) of European alleles, including 7 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/2-163136505-C-G). This variant is present in ClinVar (Variation ID:261563) with at least 2 labs classifying this variant as Benign. Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant alters the consensus splice sequence (+/- 1,2) which is predicted to result in an absent or abnormal protein. However, there is limited evidence for this gene and to support loss of function (LOF) as a known disease mechanism. In vitro functional studies suggest that this variant will impact the protein by causing an in-frame loss of 39 amino acids and the skipping of exon 8; thus potentially disrupting signaling function, enzymatic activity and protein stability (Asgari 2017 PMID:28716935). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV004555860	SCV005045048	uncertain significance	Immunodeficiency 95	2024-01-05	criteria provided, single submitter	clinical testing	The IFIH1 c.1641+1G>C variant has been reported in three unrelated individuals that required noninvasive ventilatory support for respiratory syncytial virus bronchiolitis (Asgari S et al., PMID: 28716935). This variant occurs within the canonical splice donor site, which is predicted to cause skipping of the eighth exon, leading to an in-frame transcript. The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 1.07% in the European non-Finnish population. This variant has been reported in the ClinVar database as a germline variant of uncertain significance for Immunodeficiency 95 and benign for Aicardi-Goutieres syndrome 7 and Singleton-Merten syndrome 1. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000545421	SCV001448260	uncertain significance	Singleton-Merten syndrome 1; Aicardi-Goutieres syndrome 7	2020-10-04	flagged submission	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000245122	SCV001549363	benign	not specified		no assertion criteria provided	clinical testing	The IFIH1 c.1641+1G>C variant was identified in the literature found to be associated with Type 1 Diabetes in a large case-control study (Nejentsev_2009_PMID:19264985). The variant was identified in dbSNP (ID: rs35337543), LOVD 3.0 (classified as likely benign and a VUS) and ClinVar (classified as benign by Prevention Genetics and Invitae, as uncertain significance by Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago and as likely pathogenic by CeGaT Praxis fuer Humangenetik Tuebingen). The variant was not identified in other databases. The variant was identified in control databases in 1888 of 281368 chromosomes (7 homozygous) at a frequency of 0.00671 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 1379 of 128286 chromosomes (freq: 0.01075), Latino in 332 of 35158 chromosomes (freq: 0.009443), Other in 66 of 7164 chromosomes (freq: 0.009213), African in 70 of 24914 chromosomes (freq: 0.00281), Ashkenazi Jewish in 13 of 10352 chromosomes (freq: 0.001256), South Asian in 16 of 30490 chromosomes (freq: 0.000525), European (Finnish) in 11 of 25070 chromosomes (freq: 0.000439), and East Asian in 1 of 19934 chromosomes (freq: 0.00005). The c.1641+1G>C variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. Further, functional analysis of IFIH1 RNA has demonstrated aberrant splicing of the IFIH1 transcript with the c.1641+1G>C variant (Downes_2010_PMID:20844740). However, exon skipping due to loss of the splice consensus sequence is predicted to preserve the reading frame. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001778865	SCV002014779	risk factor	Multisystem inflammatory syndrome in children	2021-11-14	flagged submission	research
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000584843	SCV002818173	likely pathogenic	not provided	2022-12-17	flagged submission	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV003114429	SCV003798464	likely risk allele	Susceptibility to severe COVID-19	2022-07-01	no assertion criteria provided	research