Submissions for variant NM_002294.3(LAMP2):c.253G>A (p.Gly85Ser)

gnomAD frequency: 0.00001  dbSNP: rs371149731

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480236	SCV000565696	uncertain significance	not specified	2016-10-27	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the LAMP2 gene. The G85S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, this variant was previously identified in one other unrelated individual referred for HCM genetic testing at GeneDx. The G85S variant was not observed at a significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G85S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species, and Serine is the wild-type amino acid at this position in at least one species. Furthermore, in silico analysis predicts this variant likely does not alter the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Ambry Genetics	RCV002431391	SCV002740579	uncertain significance	Cardiovascular phenotype	2020-12-04	criteria provided, single submitter	clinical testing	The p.G85S variant (also known as c.253G>A), located in coding exon 3 of the LAMP2 gene, results from a G to A substitution at nucleotide position 253. The glycine at codon 85 is replaced by serine, an amino acid with similar properties. Based on data from gnomAD, the A allele has an overall frequency of 0.0005% (1/183453) total alleles studied, with 0 hemizygotes observed. The highest observed frequency was 0.001% (1/81916) of European (non-Finnish) alleles. This amino acid position is not well conserved in available vertebrate species, and serine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002526517	SCV003286151	uncertain significance	Danon disease	2022-03-11	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 85 of the LAMP2 protein (p.Gly85Ser). This variant is present in population databases (rs371149731, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with LAMP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 418563).