Submissions for variant NM_003632.3(CNTNAP1):c.2901_2902del (p.Cys968fs)

gnomAD frequency: 0.00005  dbSNP: rs751050956

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000492827	SCV000582787	pathogenic	not provided	2023-06-22	criteria provided, single submitter	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; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31397905, 28374019, 24319099, 34930662, 33820833, 31618753)
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000186508	SCV000996123	pathogenic	Lethal congenital contracture syndrome 7	2018-03-30	criteria provided, single submitter	clinical testing	This frameshifting variant is predicted to result in a premature stop codon and is therefore considered a loss-of-function mutation. This variant has been previously reported as a homozygous change in three siblings with arthrogryposis, hypotonia, respiratory distress, and feeding difficulties (PMID: 24319099). It is present as a heterozygous change in the gnomAD population database at a frequency of 0.003% (7/277236). Based on the available evidence, the c.2901_2902delCT (p.Cys968PhefsTer11) variant is classified as a pathogenic change.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000186508	SCV001442523	pathogenic	Lethal congenital contracture syndrome 7	2020-09-30	criteria provided, single submitter	research	ACMG codes:PVS1; PM2; PM3; PP1S
DASA	RCV001813766	SCV002061234	pathogenic	Neuropathy, congenital hypomyelinating, 3	2022-01-05	criteria provided, single submitter	clinical testing	The c.2901_2902del;p.(Cys968Phefs*11) is a null frameshift variant (NMD) in the CNTNAP1 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 204313; OMIM: 602346.0003; PMID: 24319099) - PS4_moderate. This variant is not present in population databases (rs751050956, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The p.(Cys968Phefs*11) was detected in trans with a pathogenic variant (PMID: 24319099) - PM3.The variant co-segregated with disease in multiple affected family members (PMID: 24319099) - PP1_strong. In summary, the currently available evidence indicates that the variant is pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000492827	SCV002241901	pathogenic	not provided	2020-11-26	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Cys968Phefs*11) in the CNTNAP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CNTNAP1 are known to be pathogenic (PMID: 24319099). This variant is present in population databases (rs751050956, ExAC 0.004%). This variant has been observed in individual(s) with CNTNAP1-related conditions (PMID: 24319099, 31397905). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 204313).
Laboratoire de Génétique Moléculaire, CHU Bordeaux	RCV000492827	SCV002568824	pathogenic	not provided		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001813766	SCV004099810	pathogenic	Neuropathy, congenital hypomyelinating, 3	2023-09-13	criteria provided, single submitter	clinical testing	Variant summary: CNTNAP1 c.2901_2902delCT (p.Cys968PhefsX11) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 2e-05 in 251486 control chromosomes (gnomAD). c.2901_2902delCT has been reported in the literature in an individual(s) affected with Neuropathy, Congenital Hypomyelinating, 3 who was compound heterozygous with a pathogenic gross deletion variant (Bowling_2022). The following publication has been ascertained in the context of this evaluation (PMID: 34930662). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV001813766	SCV004807638	pathogenic	Neuropathy, congenital hypomyelinating, 3	2024-03-29	criteria provided, single submitter	clinical testing
OMIM	RCV000186508	SCV000240027	pathogenic	Lethal congenital contracture syndrome 7	2014-05-01	no assertion criteria provided	literature only