Submissions for variant NM_000372.5(TYR):c.1112A>C (p.Asn371Thr)

gnomAD frequency: 0.00001  dbSNP: rs61754387

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085897	SCV002236675	pathogenic	not provided	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 371 of the TYR protein (p.Asn371Thr). This variant is present in population databases (rs61754387, gnomAD 0.002%). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 29345414). 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: 3798). 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.Asn371 amino acid residue in TYR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29345414). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526588	SCV005039211	likely pathogenic	Oculocutaneous albinism	2024-03-22	criteria provided, single submitter	clinical testing	Variant summary: TYR c.1112A>C (p.Asn371Thr) results in a non-conservative amino acid change located in the Tyrosinase copper-binding domain (IPR002227) of 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 8e-06 in 250990 control chromosomes (gnomAD). c.1112A>C has been reported in the literature in individuals affected with Oculocutaneous Albinism (Oetting_1991, King_2003). These data indicate that the variant may be associated with disease. Another missense changer affecting this residue (p.Asn371Tyr) has been determined to be pathogenic, suggesting this is a functionally important residue. 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: 1642278, 8434585, 13680365, 1676041). ClinVar contains an entry for this variant (Variation ID: 3798). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005007820	SCV005631376	likely pathogenic	Tyrosinase-negative oculocutaneous albinism; Oculocutaneous albinism type 1B; SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	2024-03-20	criteria provided, single submitter	clinical testing
OMIM	RCV000004002	SCV000024168	pathogenic	Tyrosinase-negative oculocutaneous albinism	1992-07-15	no assertion criteria provided	literature only
Retina International	RCV000085897	SCV000118040	not provided	not provided		no assertion provided	not provided
PreventionGenetics, part of Exact Sciences	RCV004739289	SCV005342550	likely pathogenic	TYR-related disorder	2024-08-26	no assertion criteria provided	clinical testing	The TYR c.1112A>C variant is predicted to result in the amino acid substitution p.Asn371Thr. This variant has been reported in an individual with oculocutaneous albinism (Figure 2, Oetting et al. 1993. PubMed ID: 8434585). An alternate substitution of this amino acid (p.Asn371Tyr) has been reported many times in individuals with oculocutaneous albinism (Table S1, Lasseaux et al. 2018. PubMed ID: 29345414). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Given the evidence, we interpret this variant as likely pathogenic.