Submissions for variant NM_016366.3(CABP2):c.637+1G>T

gnomAD frequency: 0.00102  dbSNP: rs149712664

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000733246	SCV000861289	likely pathogenic	not provided	2018-05-14	criteria provided, single submitter	clinical testing
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	RCV000790515	SCV000929845	pathogenic	Autosomal recessive nonsyndromic hearing loss 93		criteria provided, single submitter	research
Molecular Diagnostics Lab, Aalborg University Hospital	RCV000790515	SCV001335281	pathogenic	Autosomal recessive nonsyndromic hearing loss 93	2020-06-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000733246	SCV001397367	pathogenic	not provided	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 6 of the CABP2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs149712664, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. Disruption of this splice site has been observed in individual(s) with deafness (PMID: 22981119). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 597198). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 6 and introduces a new termination codon (PMID: 22981119). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Center for Statistical Genetics, Columbia University	RCV000790515	SCV001622777	pathogenic	Autosomal recessive nonsyndromic hearing loss 93		criteria provided, single submitter	clinical testing
GeneDx	RCV000733246	SCV001810803	pathogenic	not provided	2022-01-17	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30096381, 22981119, 31053783, 30303587, 31661684, 33269433, 32991204, 32681043, 32860223, 33666369)
Revvity Omics, Revvity	RCV000790515	SCV002018024	pathogenic	Autosomal recessive nonsyndromic hearing loss 93	2020-01-27	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000733246	SCV002544579	pathogenic	not provided	2024-12-01	criteria provided, single submitter	clinical testing	CABP2: PM3:Strong, PP1:Strong, PVS1:Strong, PM2:Supporting, PS3:Supporting
Neuberg Centre For Genomic Medicine, NCGM	RCV000790515	SCV004176488	pathogenic	Autosomal recessive nonsyndromic hearing loss 93	2023-03-01	criteria provided, single submitter	clinical testing	The invariant splice donor c.637+1G>T variant in CABP2 gene has been observed homozygous / compound heterozygous state in individual(s) with deafness (Schrauwen et. al., 2012). It has also been observed to segregate with disease in related individuals. Studies have shown that disruption of this splice site results in skipping of exon 6 and introduces a new termination codon (Schrauwen et. al., 2012). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (Buratti et. al., 2007). The c.637+1G>T variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.1% in gnomAD exomes database. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant in CABP2 gene, the molecular diagnosis is not confirmed.
Mayo Clinic Laboratories, Mayo Clinic	RCV000733246	SCV004225740	pathogenic	not provided	2022-09-08	criteria provided, single submitter	clinical testing	PP1, PM3, PS4_moderate, PVS1_strong
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000790515	SCV004806896	pathogenic	Autosomal recessive nonsyndromic hearing loss 93	2024-03-26	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000733246	SCV005197350	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV000790515	SCV005397456	pathogenic	Autosomal recessive nonsyndromic hearing loss 93	2023-05-19	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (G>T) at the +1 canonical donor splice site of the sixth of seven exons of the CABP2 gene. The disruption of this donor site is expected to lead to the out of frame skipping of exon 6 resulting in the production of a truncated protein that lacks the calcium binding domains critical for calcium sensing by CABP2 (PMID: 22981119). This is a previously reported variant (ClinVar) that has been observed in individuals with hearing loss (PMID: 33666369, 32681043, 30303587). In addition, this variant segregated with hearing loss across multiple individuals in multiple families (PMID: 22981119, 32991204, 35150090, 33269433). This variant is present in 291 of 282,396 alleles (0.1%) in the gnomAD control population dataset. This variant is particularly common in the European Finnish population (0.3%); this relatively high minor allele frequency is attributed to stochastic demographic processes (PMID: 35150090). R, protein, and whole cell alysis confirms that this variant results in the skipping of exon 6, alters calcium affinity of the protein product, and disrupts calcium dependent ictivation of calcium channels (PMID: 22981119). Given this information, we consider this a pathogenic variant. ACMG Criteria: PP1, PS3, PVS1
OMIM	RCV000790515	SCV000056718	pathogenic	Autosomal recessive nonsyndromic hearing loss 93	2012-10-05	no assertion criteria provided	literature only
Laboratory of Prof. Karen Avraham, Tel Aviv University	RCV000790515	SCV001337670	pathogenic	Autosomal recessive nonsyndromic hearing loss 93	2019-07-06	no assertion criteria provided	research	Recessive, compound heterozygous with NM_001318496.1: c.250G>A; congenital, variable SNHL
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291207	SCV001479632	likely pathogenic	Hearing loss, autosomal recessive		no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000733246	SCV001955407	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000733246	SCV001970447	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003947951	SCV004758150	pathogenic	CABP2-related disorder	2024-05-17	no assertion criteria provided	clinical testing	The CABP2 c.637+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant segregated with autosomal recessive hearing loss in seven families with 15 affected and 11 unaffected individuals (Schrauwen. 2012. PubMed ID: 22981119; Ramzan. 2020. PubMed ID: 32681043; Sheyanth. 2021. PubMed ID: 33666369; Bharadwaj. 2022. PubMed ID: 35150090). This variant is reported in 0.33% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic.