Submissions for variant NM_000550.3(TYRP1):c.1057_1060del (p.Asn353fs)

dbSNP: rs387906562

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000019164	SCV000245678	pathogenic	Oculocutaneous albinism type 3	2014-08-04	criteria provided, single submitter	clinical testing	The Asn353ValfsX31 variant in TYRP1 has been reported in 1 Asian individual with oculocutaneous albinism type III (compound heterozygous) (Rooryck 2008). The Asn353ValfsX31 variant was not identified in large population studies. This frameshift variant is predicted to alter the protein’s amino acid sequence beginning at position 353 and lead to a premature termination codon 31 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. _x000D_In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) for oculocutaneous albinism type III acting in a recessive manner.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001380027	SCV001577954	pathogenic	not provided	2025-01-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn353Valfs*31) in the TYRP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TYRP1 are known to be pathogenic (PMID: 8651291, 9345097). This variant is present in population databases (rs752724988, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with oculocutaneous albinism (PMID: 18821858, 19533799). ClinVar contains an entry for this variant (Variation ID: 17598). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002490389	SCV002779340	pathogenic	Oculocutaneous albinism type 3; MELANESIAN BLOND HAIR	2021-11-04	criteria provided, single submitter	clinical testing
GeneDx	RCV001380027	SCV003935428	pathogenic	not provided	2023-06-22	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 18821858, 19533799, 34426522, 31589614)
Centro Nacional de Genética Medica "Dr. Eduardo E. Castilla", Administración Nacional de Laboratorios e Institutos de Salud	RCV000019164	SCV005908044	pathogenic	Oculocutaneous albinism type 3	2024-08-01	criteria provided, single submitter	research	The c.1057_1060del, p.Asn353Valfs*31, variant found is located in exon 5 of the TYRP1 gene. The gene is haploinsufficient and as a consequence of this variant there would be no translation and consequently, a lack of protein (PVS1). Loss-of-function variants are known to be a mechanism of pathogenicity in this gene (70 pathogenic null variants reported in ClinVar). The variant is associated with an autosomal recessive type of inheritance and was reported in the literature in trans with another pathogenic variant (PM3). The variant found is found at very low frequency in population databases such as GnomAD, ExAc or 1000 genomes (PM2_Supporting) and has been reported as pathogenic in ClinVar (rs387906562) related to oculocutaneous albinism type 3 (OCA3) (OMIM #203290), an autosomal recessive inheritance pathology that affects melanin biosynthesis and leads to reduced pigmentation in hair, skin and eyes. The patient's phenotype is consistent with oculocutaneous albinism type 3, and the TYRP1 gene is closely associated with the condition (PP4). Patient with albinism.
OMIM	RCV000019164	SCV000039452	pathogenic	Oculocutaneous albinism type 3	2009-07-01	no assertion criteria provided	literature only
Clinical Genetics, Academic Medical Center	RCV001380027	SCV001923397	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001380027	SCV001963948	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004752713	SCV005361033	pathogenic	TYRP1-related disorder	2024-04-18	no assertion criteria provided	clinical testing	The TYRP1 c.1057_1060delAACA variant is predicted to result in a frameshift and premature protein termination (p.Asn353Valfs*31). This variant has been reported in individuals with oculocutaneous albinism (Rooryck et al. 2008. PubMed ID: 18821858; Chiang et al. 2009. PubMed ID: 19533799). This variant is reported in 0.020% of alleles in individuals of South Asian descent in gnomAD. Frameshift variants in TYRP1 are expected to be pathogenic. Given the evidence, we interpret this variant as pathogenic.