Submissions for variant NM_000372.5(TYR):c.131G>A (p.Ser44Asn)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV005103876	SCV005835903	likely pathogenic	not provided	2024-05-07	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 44 of the TYR protein (p.Ser44Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 24461674; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Advanced 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 at Invitae 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.Ser44 amino acid residue in TYR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15146472, 25703744; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004740885	SCV005363960	likely pathogenic	TYR-related disorder	2024-08-11	no assertion criteria provided	clinical testing	The TYR c.131G>A variant is predicted to result in the amino acid substitution p.Ser44Asn. This variant has been reported in the compound heterozygous state in an individual with oculocutaneous albinism (Okamura et al. 2014. PubMed ID: 24461674). Alternate substitutions of this amino acid residue (p.Ser44Arg and p.Ser44Gly) have also been reported in individuals with oculocutaneous albinism (Opitz et al. 2004. PubMed ID: 15146472; Shah et al. 2015. PubMed ID: 25703744). This variant has not been reported in the large population database gnomAD, indicating this variant is rare. Given the evidence, we interpret this variant as likely pathogenic.