Submissions for variant NM_000310.4(PPT1):c.739T>C (p.Tyr247His)

gnomAD frequency: 0.00001  dbSNP: rs386833665

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000726872	SCV000703755	likely pathogenic	not provided	2016-12-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000049625	SCV001387831	pathogenic	Neuronal ceroid lipofuscinosis 1	2023-09-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr247 amino acid residue in PPT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects PPT1 function (PMID: 11440996, 29631617). 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) performed at Invitae indicates that this missense variant is expected to disrupt PPT1 protein function. ClinVar contains an entry for this variant (Variation ID: 56214). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 9664077, 23857568). This variant is present in population databases (rs386833665, gnomAD 0.002%). This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 247 of the PPT1 protein (p.Tyr247His).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317068	SCV004020551	likely pathogenic	Neuronal ceroid lipofuscinosis	2023-06-06	criteria provided, single submitter	clinical testing	Variant summary: PPT1 c.739T>C (p.Tyr247His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251396 control chromosomes (gnomAD). c.739T>C has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (examples: Das_1998 and Miller_2013). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example: Das_2001). A different variant affecting the same residue c.740A>G (p.Tyr247Cys) is classified likely pathogenic in ClinVar (ID 379909), suggesting this residue may be critical for the normal protein function. The following publications have been ascertained in the context of this evaluation (PMID: 11440996, 9664077, 23857568, 29631617, 11073228). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000049625	SCV004204171	likely pathogenic	Neuronal ceroid lipofuscinosis 1	2024-03-12	criteria provided, single submitter	clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049625	SCV000082032	probable-pathogenic	Neuronal ceroid lipofuscinosis 1		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.