Submissions for variant NM_016180.5(SLC45A2):c.1256C>T (p.Pro419Leu)

gnomAD frequency: 0.00004  dbSNP: rs530738094

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002035290	SCV002228140	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 419 of the SLC45A2 protein (p.Pro419Leu). This variant is present in population databases (rs530738094, gnomAD 0.006%). This missense change has been observed in individual(s) with oculocutaneous albinism type 4 (PMID: 19865097, 21287499, 28976636). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1451395). 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%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004587269	SCV005077301	pathogenic	Oculocutaneous albinism type 4	2024-04-08	criteria provided, single submitter	clinical testing	Variant summary: SLC45A2 c.1256C>T (p.Pro419Leu) 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-05 in 251482 control chromosomes (gnomAD). c.1256C>T has been reported in the literature in multiple individuals affected with Oculocutaneous albinism type 4 (e.g. Lasseuax_2018, Wei_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 34838614, 29345414). ClinVar contains an entry for this variant (Variation ID: 1451395). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV002035290	SCV005325073	likely pathogenic	not provided	2023-06-22	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: 21287499, 34838614, 19865097, 28976636)
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004587269	SCV005416626	pathogenic	Oculocutaneous albinism type 4		criteria provided, single submitter	clinical testing	PM2_Supporting+PM3_VeryStrong+PP4+PP3_Moderate
Fulgent Genetics, Fulgent Genetics	RCV005031988	SCV005671157	pathogenic	SKIN/HAIR/EYE PIGMENTATION 5, BLACK/NONBLACK HAIR; Oculocutaneous albinism type 4	2024-04-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004756328	SCV005362599	likely pathogenic	SLC45A2-related disorder	2024-08-02	no assertion criteria provided	clinical testing	The SLC45A2 c.1256C>T variant is predicted to result in the amino acid substitution p.Pro419Leu. This variant has been reported in the compound heterozygous state in individuals with oculocutaneous albinism (Wei et al. 2010. PubMed ID: 19865097; mislabeled as p.Pro491Leu, Marti et al. 2017. PubMed ID: 28976636; Table S1, Wei et al 2021. PubMed ID: 34838614). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD. Given the evidence, we interpret this variant as likely pathogenic.