Submissions for variant NM_016180.5(SLC45A2):c.113A>G (p.His38Arg)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003555181	SCV004293697	likely pathogenic	not provided	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 38 of the SLC45A2 protein (p.His38Arg). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of oculocutaneous albinism (PMID: 19610114, 29345414; Invitae). 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 SLC45A2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SLC45A2 function (PMID: 19610114). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701733	SCV005203849	pathogenic	Oculocutaneous albinism type 4	2024-07-02	criteria provided, single submitter	clinical testing	Variant summary: SLC45A2 c.113A>G (p.His38Arg) results in a non-conservative amino acid change in 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 4e-06 in 250792 control chromosomes. c.113A>G has been reported in the literature in two homozygous individuals affected with Oculocutaneous albinism type 4 (Konno_2009, Lasseuax_2018). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in mutant protein functionally incapable of melanin synthesis in cultured melanocyte (Konno_2009). The following publications have been ascertained in the context of this evaluation (PMID: 19610114, 29345414). ClinVar contains an entry for this variant (Variation ID: 2734711). Based on the evidence outlined above, the variant was classified as pathogenic.