Submissions for variant NM_000049.4(ASPA):c.502C>T (p.Arg168Cys)

dbSNP: rs937670540

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV001004409	SCV001163412	pathogenic	Spongy degeneration of central nervous system		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001093137	SCV001249972	pathogenic	not provided	2019-11-01	criteria provided, single submitter	clinical testing
Invitae	RCV001004409	SCV001575909	pathogenic	Spongy degeneration of central nervous system	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 168 of the ASPA protein (p.Arg168Cys). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individuals with Canavan disease (PMID: 8659549, 16854607; Invitae). ClinVar contains an entry for this variant (Variation ID: 813438). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ASPA protein function. Experimental studies have shown that this missense change affects ASPA function (PMID: 8659549). This variant disrupts the p.Arg168 amino acid residue in ASPA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10909858, 28101991). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV001004409	SCV002032873	pathogenic	Spongy degeneration of central nervous system	2021-11-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001004409	SCV002060037	likely pathogenic	Spongy degeneration of central nervous system	2021-11-11	criteria provided, single submitter	clinical testing	NM_000049.2(ASPA):c.502C>T(R168C) is a missense variant classified as likely pathogenic in the context of Canavan disease. R168C has been observed in cases with relevant disease (PMID: 27531131, 16854607, 8659549, 28101991). Functional assessments of this variant are available in the literature (PMID: 8659549). Internal structural analysis of the variant is supportive of pathogenicity. R168C has been observed in population frequency databases (gnomAD: FIN 0.005%). In summary, NM_000049.2(ASPA):c.502C>T(R168C) is a missense variant that has both functional and internal structural support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Fulgent Genetics, Fulgent Genetics	RCV001004409	SCV002780125	likely pathogenic	Spongy degeneration of central nervous system	2021-08-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002551712	SCV003582170	likely pathogenic	Inborn genetic diseases	2021-12-08	criteria provided, single submitter	clinical testing	The c.502C>T (p.R168C) alteration is located in exon 3 (coding exon 3) of the ASPA gene. This alteration results from a C to T substitution at nucleotide position 502, causing the arginine (R) at amino acid position 168 to be replaced by a cysteine (C). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in the homozygous and compound heterozygous states in patients with Canavan disease (Kaul, 1996; Zeng, 2006; Zaki, 2017). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, this alteration is located at a position and in a region critical for protein function (Wijayasinghe, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.