Submissions for variant NM_000152.5(GAA):c.761C>T (p.Ser254Leu)

gnomAD frequency: 0.00006  dbSNP: rs577915581

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000285433	SCV000407271	likely pathogenic	Glycogen storage disease, type II	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000498412	SCV000590492	uncertain significance	not provided	2021-06-18	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29122469, 18458862, 25466677, 27183828, 24513544, 29451150, 29124014, 31637888, 31980526)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000285433	SCV000626639	pathogenic	Glycogen storage disease, type II	2022-08-28	criteria provided, single submitter	clinical testing	The c.761C>T sequence change replaces serine with leucine at codon 254 of the GAA protein (p.Ser254Leu). The serine residue is highly conserved and there is a large physiochemical difference between serine and leucine. This variant is present in population databases (rs577915581, gnomAD 0.3%). The c.761C>T (p.Ser254Leu) variant frequently co-occurs with the c.752C>T (p.Ser251Leu) variant (rs200856561) in cis (on the same chromosome), which is known as the c.[752C>T;761C>T] haplotype. This haplotype has been reported in the literature as homozygous or in combination with other GAA variants in multiple individuals affected with Pompe disease (PMID: 24513544, 29124014, 27183828). The clinical significance of the c.761C>T variant alone is unclear. ClinVar contains an entry for this variant (Variation ID: 325782). ClinVar contains an entry for this variant (Variation ID: 325782). While the c.761C>T (p.Ser254Leu) variant alone has not been shown to affect GAA protein function, the c.[752C>T;761C>T] haplotype has been reported to reduce enzyme activity (PMID: 22644586). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this haplotype has been classified as Pathogenic.
Baylor Genetics	RCV000285433	SCV001528212	uncertain significance	Glycogen storage disease, type II	2018-01-24	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genome-Nilou Lab	RCV000285433	SCV001810440	likely pathogenic	Glycogen storage disease, type II	2021-07-22	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000498412	SCV002501222	likely pathogenic	not provided	2022-01-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265734	SCV002547857	uncertain significance	not specified	2024-08-19	criteria provided, single submitter	clinical testing	Variant summary: GAA c.761C>T (p.Ser254Leu) results in a non-conservative amino acid change located in the Galactose mutarotase, N-terminal barrel domain (IPR031727) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 282470 control chromosomes, predominantly at a frequency of 0.0028 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (0.00019 vs 0.0042), allowing no conclusion about variant significance. c.761C>T has been reported in the literature as a complex allele in cis with c.752C>T (p.Ser251Leu) in settings of newborn screening for Glycogen Storage Disease, Type 2 (Pompe Disease) (example, Labrousse_2010, Chien_2011, Liao_2014). This complex allele has been observed as a homozygous and compound heterozygous genotype in the ascertained reports among newborns with screening enzyme activity below the cutoff value (example, Liao_2014). These report(s) do not provide unequivocal conclusions about association of the variant in isolation with Glycogen Storage Disease, Type 2 (Pompe Disease). Co-occurrences of this complex allele in cis with other pathogenic variant(s) have been reported in the literature (GAA c.1411_1414del, p.E471PfsX5), providing supporting evidence for a benign role (example, Larousse_2010, Liao_2014, Yue_2024). To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31228295, 21232767, 22644586, 20080426, 24513544, 38186848). ClinVar contains an entry for this variant (Variation ID: 325782). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000498412	SCV004224256	pathogenic	not provided	2022-11-22	criteria provided, single submitter	clinical testing
Counsyl	RCV000285433	SCV001132197	likely pathogenic	Glycogen storage disease, type II	2019-06-11	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751466	SCV005345978	uncertain significance	GAA-related disorder	2024-06-14	no assertion criteria provided	clinical testing	The GAA c.761C>T variant is predicted to result in the amino acid substitution p.Ser254Leu. This variant has been reported in individuals with glycogen storage disease 2, also called Pompe Disease (Tang et al. 2020. PubMed ID: 33073007; Fukuhara et al. 2017. PubMed ID: 29124014; Peng et al. 2016. PubMed ID: 27183828; Lee et al. 2019. PubMed ID: 31637888). This variant is reported in 0.28% of alleles in individuals of East Asian descent in gnomAD. The c.761C>T variant frequently occurs in cis with the c.752C>T (p.Ser251Leu) variant, and is known as the c.[752C>T;761C>T] haplotype. This haplotype has been reported in the homozygous or compound heterozygous state in multiple individuals with Pompe disease (Fukuhara et al. 2017. PubMed ID: 29124014; Peng et al. 2016. PubMed ID: 27183828). Of note, the c.[752C>T; 761C>T] (p.[Ser251Leu; Ser254Leu]) haplotype has been reported to be in cis with the c.1411_1414delGAGA variant (Labrousse et al. 2009. PubMed ID: 20080426; Chien et al. 2014. PubMed ID: 25466677; Mori et al. 2017. PubMed ID: 29122469). The c.[752C>T;761C>T] haplotype has been reported to significantly reduce GAA enzyme activity to 1.7-3.3% of wild-type activity (Kroos M et al 2012. PubMed ID: 22644586). ClinVar classifications for the c.761C>T variant range from uncertain, to likely pathogenic, to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/325782/), while one lab has classified the c.[752C>T;761C>T] haplotype as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/1321358/). Although we suspect that this variant may be pathogenic, at this time the clinical significance of this variant is uncertain.