Submissions for variant NM_001349338.3(FOXP1):c.1652+5G>A

dbSNP: rs794727216

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000358706	SCV000226844	uncertain significance	not provided	2015-01-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000358706	SCV000330183	pathogenic	not provided	2023-05-26	criteria provided, single submitter	clinical testing	Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34580403, 35991577)
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253743	SCV001429602	likely pathogenic	Intellectual disability-severe speech delay-mild dysmorphism syndrome	2019-04-03	criteria provided, single submitter	clinical testing	This variant was identified as de novo (maternity and paternity confirmed).
3billion, Medical Genetics	RCV001253743	SCV002012174	likely pathogenic	Intellectual disability-severe speech delay-mild dysmorphism syndrome	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with supporting evidence (ClinVar ID: VCV000194897.5, PS1_P). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2). In silico tools do not predict the variant to alter splicing and produce an abnormal transcript (SpliceAI:0.8, PP3). The variant has been reported to co-segregate with the disease in three similarly affected siblings in the same family (3billion dataset, PP1). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genetic Services Laboratory, University of Chicago	RCV001818420	SCV002069152	uncertain significance	not specified	2019-09-17	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001253743	SCV002557697	pathogenic	Intellectual disability-severe speech delay-mild dysmorphism syndrome	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with intellectual disability with language impairment and with or without autistic features (MIM#613670). Loss of function due to haploinsufficiency has been demonstrated, however dominant negative has also been suggested (PMIDs: 26647308, 31199603). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0704 - Another non-canonical splice site variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The c.1652+5G>C variant has been reported as likely pathogenic in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as likely pathogenic/pathogenic in three individuals, and has been shown to be de novo in two of the individuals (ClinVar, Decipher). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (by research trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001253743	SCV002818254	likely pathogenic	Intellectual disability-severe speech delay-mild dysmorphism syndrome	2024-10-04	criteria provided, single submitter	research	PM2,PP3,PS2
Labcorp Genetics (formerly Invitae), Labcorp	RCV000358706	SCV003326749	pathogenic	not provided	2024-09-08	criteria provided, single submitter	clinical testing	This sequence change falls in intron 18 of the FOXP1 gene. It does not directly change the encoded amino acid sequence of the FOXP1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with FOXP1-related conditions (PMID: 34580403, 35991577; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 194897). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV003258680	SCV003969184	pathogenic	Inborn genetic diseases	2023-06-01	criteria provided, single submitter	clinical testing	The c.1652+5G>A intronic alteration consists of a G to A substitution 5 nucleotides after exon 18 (coding exon 13) in the FOXP1 gene. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in two individuals with features consistent with FOXP1-related neurodevelopmental disorder (Pode-Shakked, 2021; Chen, 2022). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000358706	SCV005042438	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	FOXP1: PS2:Very Strong, PM2, PS4:Moderate, PP3, PS1:Supporting, PS3:Supporting
Pediatric Genetics Clinic, Sheba Medical Center	RCV001253743	SCV001712178	likely pathogenic	Intellectual disability-severe speech delay-mild dysmorphism syndrome	2021-05-13	no assertion criteria provided	clinical testing