Submissions for variant NM_000049.4(ASPA):c.634+1G>T (rs753871454)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000666161	SCV000790407	pathogenic	Spongy degeneration of central nervous system	2017-03-24	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000666161	SCV000914760	likely pathogenic	Spongy degeneration of central nervous system	2017-12-05	criteria provided, single submitter	clinical testing	The ASPA c.634+1G>T variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.634+1G>T variant has been reported in three studies and is found in a homozygous state in three unrelated probands (Rady et al. 2000; Kaya et al. 2008; Madhavarao et al. 2009). The probands were all clinically diagnosed with Canavan disease and have variable phenotypic expressivity. The variant was also identified in a heterozygous state in the unaffected parents and an unaffected sibling of one of the probands (Rady et al. 2000). Control data are unavailable for this variant, which is reported at a frequency of 0.000011 in the Total population from the Genome Aggregation Database. Based on the evidence and the potential impact of splice donor variants, the c.634+1G>T variant is classified as likely pathogenic for Canavan disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America	RCV000780869	SCV000918494	pathogenic	Canavan Disease, Familial Form	2017-12-07	criteria provided, single submitter	clinical testing	Variant summary: The ASPA c.634+1G>T variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict the complete loss of a cannonical splice donor site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 3/277022 control chromosomes at a frequency of 0.0000108, which does not exceed the estimated maximal expected allele frequency of a pathogenic ASPA variant (0.0079057). This variant has been reported in multiple Canavan disease patients both as homozygotes and compound heterozygotes. Taken together, this variant is classified as pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV001093139	SCV001249974	pathogenic	not provided	2018-04-01	criteria provided, single submitter	clinical testing
Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence,	RCV000666161	SCV001250604	uncertain significance	Spongy degeneration of central nervous system		no assertion criteria provided	clinical testing