ClinVar Genomic variation as it relates to human health

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

NRXN1 NM_001135659.2 exon 15 p.His885Tyr (c.2653C>T): This variant has been reported in the literature in at least 1 individual with autism spectrum disorder (ASD), segregating with disease in 1 affected family member. However, this family member did not meet clinical criteria for ASD (Jiang 2013 PMID:23849776). This variant is present in 0.1% (78/68024) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/2-50497679-G-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:20245). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

The c.2653C>T (p.H885Y) alteration is located in exon 15 (coding exon 14) of the NRXN1 gene. This alteration results from a C to T substitution at nucleotide position 2653, causing the histidine (H) at amino acid position 885 to be replaced by a tyrosine (Y). The alteration is ultra rare in population databases:_x000D_ The NRXN1 c.2653C>T alteration was observed in 72 out of 120,252 total alleles studied (0.06%) in the Exome Aggregation Consortium (ExAC) database, with a frequency of 69/66,496 (0.1%) in the European (Non-Finnish) sub-population. Based on data from the NHLBI Exome Sequencing Project (ESP), the NRXN1 c.2653C>T alteration was observed in 12 among 12,074 total alleles studied (0.1%). Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project. Rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012; please note that some variants may appear to be rare due to ethnic underrepresentation in the database)._x000D_ IF USED, PULL THESE INTO REFERENCES:_x000D_ Kryukov GV, et al. (2007) Am J Hum Genet 80:727-739. Tennessen JA, et al. (2012) Science 337(64):64-69. The alteration has been observed in affected individuals: _x000D_ The NRXN1 c.2653C>T (p.H885Y) alteration has been reported in a proband with autism spectrum disorder and his brother with a learning disability. The alteration was found to be inherited from the brothers' unaffected father (Jiang, 2013). The altered amino acid is conserved throughout evolution:_x000D_ The p.H885 amino acid is conserved in available vertebrate species. In silico prediction is conflicting:_x000D_ The p.H885Y alteration is predicted to be probably damaging by Polyphen and tolerated by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Reported in a patient with autism spectrum disorder, sibling with learning disabilities and their unaffected father, and in an unrelated individual with spastic paraplegia and epilepsy who was also a compound heterozygote for 2 variants in the ALDH18A1 gene (PMID: 23849776, 29754261); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variant in a gene in which most reported pathogenic variants are truncating/loss-of-function; This variant is associated with the following publications: (PMID: 29754261, 34168285, 23849776)

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.

Variant interpreted as Uncertain significance and reported on 07-13-2019 by lab or GTR ID 26957. GenomeConnect - Association for Creatine Deficiencies assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.