Submissions for variant NM_002778.4(PSAP):c.1A>G (p.Met1Val)

dbSNP: rs121918106

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001066448	SCV001231459	pathogenic	Sphingolipid activator protein 1 deficiency	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the PSAP mRNA. The next in-frame methionine is located at codon 76. This variant is present in population databases (rs121918106, gnomAD 0.006%). Disruption of the initiator codon has been observed in individuals with saposin C deficiency (PMID: 1371116, 17616409, 20484222). ClinVar contains an entry for this variant (Variation ID: 860182). Studies have shown that disruption of the initiator codon alters PSAP gene expression (PMID: 20484222). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001833645	SCV002819397	pathogenic	Metachromatic leukodystrophy	2022-12-09	criteria provided, single submitter	clinical testing	Variant summary: PSAP c.1A>G (p.Met1Val) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. An alternative downstream in-frame start codon (Met76) is located in the encoded protein. An activation of this potential downstream translation initiation site would result in a shortened protein missing the first 75 amino acids from the protein sequence, predicted to disrupt the N-terminal saposin A-type domain (IPR003119) of the encoded protein. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.5e-06 in 154492 control chromosomes (gnomAD). c.1A>G has been reported in the literature in the compound heterozygous state in trans with a pathogenic variant in an individual affected with Metachromatic Leukodystrophy and in a compound heterozygous individual affected with Gaucher Disease, type 3 (e.g. Deconinck_2008, Vaccaro_2010). These data indicate that the variant is likely associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found this variant and another start codon variant, p.Met1Leu, both affect protein expression in a manner consistent with a null allele (e.g. Vaccaro_2010). Futhermore, the p.Met1Leu start codon variant has also been reported in patients (e.g. Vaccaro_2010) and has been classified as pathogenic (ClinVar: 13365), suggesting that variants which affect the start codon of the PSAP gene are likely to be deleterious. Two clinical diagnostic laboratories have submitted clinical-significance assessments for the c.1A>G (p.Met1Val) variant to ClinVar after 2014 without evidence for independent evaluation. Both classified the variant as pathogenic. Based on the evidence outlined above, this variant was classified as pathogenic.
Natera, Inc.	RCV001833645	SCV002088167	pathogenic	Metachromatic leukodystrophy	2021-03-26	no assertion criteria provided	clinical testing