Submissions for variant NM_000372.5(TYR):c.1209G>T (p.Arg403Ser)

gnomAD frequency: 0.00001  dbSNP: rs104894316

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000085911	SCV000491314	likely pathogenic	not provided	2016-07-22	criteria provided, single submitter	clinical testing	The R403S variant in the TYR gene has been reported previously in individuals who underwent genetic testing for oculocutaneous albinism type 1 (Opitz et al., 2004; Oetting et al., 1993; Hutton et al., 2008). The R403S variant was not observed at any significant frequency in approximately 6500 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 R403S variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved; however, in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants in nearby residues (E398V, E398G, W400L, W400C, R402G, R402L, H404N, H404P, R405L, P406L, Q408H) have been reported in the Human Gene Mutation Database in association with oculocutaneous albinism type 1 (Stenson et al., 2014), supporting the functional importance of this region of the protein. The R403S variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
CeGaT Center for Human Genetics Tuebingen	RCV000085911	SCV001248576	pathogenic	not provided	2022-01-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000004004	SCV001821968	likely pathogenic	Tyrosinase-negative oculocutaneous albinism	2021-07-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085911	SCV002136452	pathogenic	not provided	2024-09-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 403 of the TYR protein (p.Arg403Ser). This variant is present in population databases (rs104894316, gnomAD 0.007%). This missense change has been observed in individuals with oculocutaneous albinism (PMID: 1642278, 10987646, 18463683). ClinVar contains an entry for this variant (Variation ID: 3800). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TYR protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387715	SCV004100008	pathogenic	Oculocutaneous albinism	2023-09-20	criteria provided, single submitter	clinical testing	Variant summary: TYR c.1209G>T (p.Arg403Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 250392 control chromosomes. c.1209G>T has been reported at a compound heterozygous state along with different apparently pathogenic variants in multiple individuals affected with Oculocutaneous Albinism (examples, Tripathi_1992, Passmore_1999, Hutton_2008) . These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18463683, 10987646, 1642278). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003466802	SCV004207598	pathogenic	SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	2024-02-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005007821	SCV005631386	pathogenic	Tyrosinase-negative oculocutaneous albinism; Oculocutaneous albinism type 1B; SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	2024-05-29	criteria provided, single submitter	clinical testing
OMIM	RCV000004004	SCV000024170	pathogenic	Tyrosinase-negative oculocutaneous albinism	1992-07-15	no assertion criteria provided	literature only
Retina International	RCV000085911	SCV000118054	not provided	not provided		no assertion provided	not provided