Submissions for variant NM_001330078.2(NRXN1):c.600C>T (p.Gly200=)

gnomAD frequency: 0.00003  dbSNP: rs201481698

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000598907	SCV000709873	uncertain significance	not provided	2018-02-22	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the NRXN1 gene. The c.600 C>T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.600 C>T variant is observed in 28/17456 (0.2%) alleles from individuals of East Asian background, including 1 homozygous individual (Lek et al., 2016). Several in silico splice prediction models predict that c.600 C>T may create a new cryptic splice donor site in exon 2. However, in the absence of RNA/functional studies, the actual effect of c.600 C>T on splicing is unknown. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768037	SCV000898864	uncertain significance	Pitt-Hopkins-like syndrome 2; Chromosome 2p16.3 deletion syndrome	2021-03-30	criteria provided, single submitter	clinical testing	NRXN1 NM_0011356569.1 exon 2 p.Gly200= (c.600C>T): This variant has not been reported in the literature but is present in 0.1% (28/17456) of East Asian alleles, including 1 homozygote in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/2-51254812-G-A). This variant is present in ClinVar (Variation ID:503668). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is a silent variant and does not change the amino acid, reducing the probability that this variant is disease causing. However, computational tools designed to predict splicing suggest a potential effect from this variant. Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080918	SCV001011300	benign	Pitt-Hopkins-like syndrome 2	2025-01-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001080918	SCV001299260	uncertain significance	Pitt-Hopkins-like syndrome 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Ambry Genetics	RCV002358666	SCV002657602	likely benign	Inborn genetic diseases	2018-10-15	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.