Submissions for variant NM_001374828.1(ARID1B):c.4479G>A (p.Pro1493=)

dbSNP: rs797045277

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000416951	SCV000246523	likely pathogenic	Coffin-Siris syndrome 1	2014-12-22	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000416951	SCV000494583	pathogenic	Coffin-Siris syndrome 1	2017-01-12	criteria provided, single submitter	research
GeneDx	RCV000657879	SCV000779641	pathogenic	not provided	2022-09-07	criteria provided, single submitter	clinical testing	Affects the splice donor site and induces skipping of exon 17 causing a frameshift leading to a premature Stop codon (p.Arg1338ArgfsX76) (Hoyer et al., 2012); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30349098, 22405089, 28323383, 27474218, 29286531, 15057123, 31406558)
Ambry Genetics	RCV001266859	SCV001445039	pathogenic	Inborn genetic diseases	2024-03-12	criteria provided, single submitter	clinical testing	The c.4110G>A (p.P1370P) alteration is located in coding exon 17 of the ARID1B gene. This nucleotide substitution does not change the proline (P) at codon 1370. However, this change occurs in the last base pair of coding exon 17, which makes it likely to have some effect on normal mRNA splicing. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported as a de novo occurrence in multiple unrelated individuals with CSS (Hoyer, 2012; Mignot, 2016; Zweier, 2017). This nucleotide position is highly conserved in available vertebrate species. RNA functional analysis demonstrated that the alteration leads to out-of-frame skipping of exon 17 (Hoyer, 2012). In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Based on the available evidence, this alteration is classified as pathogenic.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000416951	SCV001448924	pathogenic	Coffin-Siris syndrome 1	2019-08-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000416951	SCV001523088	pathogenic	Coffin-Siris syndrome 1	2020-05-05	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. [PMID 22405089, 27474218, 29286531, 28323383]
Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli	RCV001420197	SCV001622617	likely pathogenic	See cases	2021-04-26	criteria provided, single submitter	clinical testing	PVS1_strong;PM2_supporting;PM6_moderate
Baylor Genetics	RCV001533021	SCV001748840	pathogenic	ARID1B-related BAFopathy	2021-06-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000416951	SCV002054319	likely pathogenic	Coffin-Siris syndrome 1	2021-07-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000416951	SCV002518514	pathogenic	Coffin-Siris syndrome 1	2022-05-04	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV001420197	SCV002577861	likely pathogenic	See cases	2021-12-10	criteria provided, single submitter	clinical testing	ACMG categories: PS5,PM2,PP3
Labcorp Genetics (formerly Invitae), Labcorp	RCV000657879	SCV003439486	pathogenic	not provided	2022-08-17	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 210291). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 17 and introduces a premature termination codon (PMID: 22405089). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant has been observed in individual(s) with clinical features of Coffin-Siris syndrome and/or Coffin-Siris syndrome (PMID: 22405089, 27474218, 28323383). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 1370 of the ARID1B mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ARID1B protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product.
PreventionGenetics, part of Exact Sciences	RCV004528976	SCV004107837	pathogenic	ARID1B-related disorder	2023-04-20	criteria provided, single submitter	clinical testing	The ARID1B c.4110G>A variant is not predicted to result in an amino acid change (p.=). This variant is predicted to weaken the canonical splice donor site (Alamut Visual Plus v1.6.1). This variant has been reported in multiple individuals with Coffin-Siris syndrome and the majority of cases were found to be de novo (see for example, Hoyer et al. 2012. PubMed ID: 22405089; Mignot et al. 2016. PubMed ID: 27474218; Tumienė et al. 2018. PubMed ID: 29286531; van der Sluijs et al. 2019. PubMed ID: 30349098). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare or absent in the general population. cDNA analyses indicated that this variant causes skipping of exon 17 and a shift to the translation reading frame (p.Arg1338Argfs*76, Hoyer et al. 2012. PubMed ID: 22405089) This variant is interpreted as pathogenic.
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV000416951	SCV005397712	pathogenic	Coffin-Siris syndrome 1	2024-02-01	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (G>A) at coding position 4479 of the ARID1B gene; this variant occurs within the donor splice site of exon 17 of 20 in the ARID1B gene. This is a previously reported variant (ClinVar 210291) that has been observed in individuals affected by Coffin-Siris syndrome (PMID: 29286531, 27474218, 31406558), intellectual disability (PMID: 22405089), and HHID syndrome (PMID: 28323383). This variant is absent from the gnomAD v4.0.0 population database (0/613012 alleles). Multiple computational tools predict that this variant will cause aberrant splicing through disruption of the intron 17 splice donor site. This prediction is confirmed through RNA studies, which show that this variant causes exon 17 to be skipped, resulting in a frameshift and early termination (p.Arg1338ArgfsTer76) (PMID: 27474218). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM2, PP3, PS2, PS3, PVS1
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415059	SCV000492573	uncertain significance	Seizure; Short stature; Failure to thrive; Constipation; Recurrent respiratory infections; Microcephaly; Decreased body weight	2015-12-29	flagged submission	clinical testing
OMIM	RCV000416951	SCV000902412	pathogenic	Coffin-Siris syndrome 1	2012-03-09	no assertion criteria provided	literature only