Submissions for variant NM_000372.5(TYR):c.1064C>T (p.Ala355Val)

gnomAD frequency: 0.00003  dbSNP: rs151206295

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000195157	SCV000249331	pathogenic	Tyrosinase-negative oculocutaneous albinism	2015-04-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778350	SCV000914550	likely pathogenic	Oculocutaneous albinism	2025-02-13	criteria provided, single submitter	clinical testing
Mendelics	RCV000195157	SCV001138403	pathogenic	Tyrosinase-negative oculocutaneous albinism	2019-05-28	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000195157	SCV001821907	likely pathogenic	Tyrosinase-negative oculocutaneous albinism	2021-07-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853121	SCV002242197	pathogenic	not provided	2024-11-04	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 355 of the TYR protein (p.Ala355Val). This variant is present in population databases (rs151206295, gnomAD 0.03%). This missense change has been observed in individuals with oculocutaneous albinism type 1A (PMID: 23504663, 27734839, 27959697). ClinVar contains an entry for this variant (Variation ID: 212520). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TYR protein function. This variant disrupts the p.Ala355 amino acid residue in TYR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9259202, 10987646, 15146472). 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	RCV003462302	SCV004207562	pathogenic	SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	2024-03-25	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005003552	SCV005631370	likely pathogenic	Tyrosinase-negative oculocutaneous albinism; Oculocutaneous albinism type 1B; SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	2024-05-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000195157	SCV000328777	pathogenic	Tyrosinase-negative oculocutaneous albinism	2014-11-12	no assertion criteria provided	clinical testing	This pathogenic variant has been previously described [PMID:9259202,23504663] and was found in trans with another pathogenic variant in TYR (NM_000372.4, c.229C>T) in an individual with autism, regression in language skills at 14mo of age, macrocephaly, joint laxity, atlantoaxial instability, fractures, delayed bone age, short stature, hip dysplasia, tyrosinase-negative oculocutaneous and cutaneous albinism and decrease pain sensitivity. A likely pathogenic de novo variant in TGFB2 (NM_003238.3, c.458G>A) was reported in the same individual. Heterozygotes for this variant are expected to be asymptomatic carriers.