Submissions for variant NM_000372.5(TYR):c.307T>C (p.Cys103Arg)

dbSNP: rs1482829698

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000512841	SCV000608612	likely pathogenic	not provided	2017-04-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317249	SCV004020591	likely pathogenic	Oculocutaneous albinism	2023-06-20	criteria provided, single submitter	clinical testing	Variant summary: TYR c.307T>C (p.Cys103Arg) 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 251290 control chromosomes (gnomAD). c.307T>C has been reported in the literature in individuals affected with Oculocutaneous Albinism (e.g., Wang_2018, Lasseaux_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. At least one other variant affecting the same amino acid residue (c.308G>A, p.Cys103Tyr) has been reported in multiple affected patients/families and has been determined to be on the pathogenic spectrum (PMIDs: 29345414, 30996339, 32552135). The following publications have been ascertained in the context of this evaluation (PMID: 29345414, 30341532). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000512841	SCV004280474	pathogenic	not provided	2025-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 103 of the TYR protein (p.Cys103Arg). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with culocutaneous albinism (PMID: 29345414, 30341532). ClinVar contains an entry for this variant (Variation ID: 444269). 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 expected to disrupt TYR protein function with a positive predictive value of 95%. This variant disrupts the p.Cys103 amino acid residue in TYR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29345414, 30996339). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV004568657	SCV005055652	likely pathogenic	SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	2024-01-16	criteria provided, single submitter	clinical testing