Submissions for variant NM_000275.3(OCA2):c.2051_2052delinsG (p.Phe684fs)

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Total submissions: 5

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001008759	SCV001168544	pathogenic	not provided	2022-04-18	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23504663)
PreventionGenetics, part of Exact Sciences	RCV003396593	SCV004112273	pathogenic	OCA2-related condition	2023-09-08	criteria provided, single submitter	clinical testing	The OCA2 c.2051_2052delinsG variant is predicted to result in a frameshift and premature protein termination (p.Phe684Cysfs*8). This variant has been reported in an individual with oculocutaneous albinism (described as c.2051T>G and c.2055delT together as a complex allele in Table 1, Simeonov et al. 2013. PubMed ID: 23504663). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in OCA2 are expected to be pathogenic. Given the evidence, we interpret this variant as pathogenic.
Baylor Genetics	RCV003467584	SCV004209039	pathogenic	SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2023-04-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003492198	SCV004240916	pathogenic	Oculocutaneous albinism	2023-12-12	criteria provided, single submitter	clinical testing	Variant summary: OCA2 c.2051_2052delinsG (p.Phe684CysfsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251236 control chromosomes. c.2051_2052delinsG has been reported in the literature in individuals affected with Oculocutaneous Albinism (Simeonov_2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV001008759	SCV004672437	pathogenic	not provided	2020-12-03	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with oculocutaneous albinism (PMID: 23504663). ClinVar contains an entry for this variant (Variation ID: 430966). This variant is present in population databases (rs772595552, ExAC 0.005%). This sequence change creates a premature translational stop signal (p.Phe684Cysfs*8) in the OCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OCA2 are known to be pathogenic (PMID: 19865097, 21541274).

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