Submissions for variant NM_000235.4(LIPA):c.683T>C (p.Phe228Ser)

dbSNP: rs2228159

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000596849	SCV000704045	uncertain significance	not provided	2018-07-05	criteria provided, single submitter	clinical testing
Counsyl	RCV000665538	SCV000789679	uncertain significance	Lysosomal acid lipase deficiency	2017-02-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001450065	SCV001053199	likely benign	Wolman disease	2024-01-31	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000665538	SCV002764287	uncertain significance	Lysosomal acid lipase deficiency	2023-05-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488716	SCV004241638	uncertain significance	not specified	2023-12-01	criteria provided, single submitter	clinical testing	Variant summary: LIPA c.683T>C (p.Phe228Ser) results in a non-conservative amino acid change located in the alpha/beta hydrolase fold-1 domain (IPR000073) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 250964 control chromosomes, predominantly at a frequency of 0.0025 within the African or African-American subpopulation in the gnomAD database. This frequency is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in LIPA causing Lysosomal Acid Lipase Deficiency (0.00021 vs 0.0027), suggesting it could be a benign polymorphism found predominately in individuals of African ancestry. c.683T>C has been reported in the literature in the heterozygous state in two individuals affected with familial hypercholesterolemia, but no diagnosis of Lysosomal Acid Lipase Deficiency (Sjouke_2016). This report does not provide unequivocal conclusions about association of the variant with Lysosomal Acid Lipase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32041611, 27423329). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Three submitters classified the variant as uncertain significance and one classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004543344	SCV004771017	uncertain significance	LIPA-related disorder	2024-01-09	criteria provided, single submitter	clinical testing	The LIPA c.683T>C variant is predicted to result in the amino acid substitution p.Phe228Ser. This variant has been reported in two individuals with hypercholesterolaemia and in an individual from a cohort being studied for dyslipidemia (Table 2, Sjouke et al. 2016. PubMed ID: 27423329; Table S4, Dron et al. 2020. PubMed ID: 32041611). This variant is reported in 0.25% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.