ClinVar Miner

Submissions for variant NM_002778.4(PSAP):c.797C>T (p.Ala266Val)

gnomAD frequency: 0.00005  dbSNP: rs772161921
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001844578 SCV002103677 uncertain significance not specified 2022-02-18 criteria provided, single submitter clinical testing Variant summary: PSAP c.797C>T (p.Ala266Val) results in a non-conservative amino acid change located in the Saposin B type, region 2 domain (IPR008138) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.7e-05 in 253760 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in PSAP causing Metachromatic Leukodystrophy (6.7e-05 vs 0.0004), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.797C>T in individuals affected with Metachromatic Leukodystrophy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV002543316 SCV003447255 uncertain significance Sphingolipid activator protein 1 deficiency 2022-07-29 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 266 of the PSAP protein (p.Ala266Val). This variant is present in population databases (rs772161921, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PSAP-related conditions. ClinVar contains an entry for this variant (Variation ID: 1343561). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV003264114 SCV003982003 uncertain significance Inborn genetic diseases 2023-04-17 criteria provided, single submitter clinical testing The c.797C>T (p.A266V) alteration is located in exon 8 (coding exon 8) of the PSAP gene. This alteration results from a C to T substitution at nucleotide position 797, causing the alanine (A) at amino acid position 266 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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