NM_000372.5(TYR):c.116G>A (p.Trp39Ter) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 17, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000520545.4

Allele description [Variation Report for NM_000372.5(TYR):c.116G>A (p.Trp39Ter)]

NM_000372.5(TYR):c.116G>A (p.Trp39Ter)

Gene:

TYR:tyrosinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q14.3

Genomic location:

Preferred name:

NM_000372.5(TYR):c.116G>A (p.Trp39Ter)

HGVS:

NC_000011.10:g.89178069G>A
NG_008748.1:g.5198G>A
NM_000372.5:c.116G>AMANE SELECT
NP_000363.1:p.Trp39Ter
NC_000011.9:g.88911237G>A
NM_000372.4:c.116G>A

Protein change:

W39*

Links:

dbSNP: rs775683960

NCBI 1000 Genomes Browser:

rs775683960

Molecular consequence:

NM_000372.5:c.116G>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000617794	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Jul 17, 2017)	germline	clinical testing	Citation Link,
SCV003440455	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 17, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 13680365, 27734839, 23504663, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000617794

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Jul 17, 2017)

germline

clinical testing

Citation Link,

SCV003440455

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 17, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Tyrosinase gene mutations in oculocutaneous albinism 1 (OCA1): definition of the phenotype.

King RA, Pietsch J, Fryer JP, Savage S, Brott MJ, Russell-Eggitt I, Summers CG, Oetting WS.

Hum Genet. 2003 Nov;113(6):502-13. Epub 2003 Sep 10.

PubMed [citation]

PMID:: 13680365

Clinical evaluation and molecular screening of a large consecutive series of albino patients.

Mauri L, Manfredini E, Del Longo A, Veniani E, Scarcello M, Terrana R, Radaelli AE, Calò D, Mingoia G, Rossetti A, Marsico G, Mazza M, Gesu GP, Cristina Patrosso M, Penco S, Piozzi E, Primignani P.

J Hum Genet. 2017 Feb;62(2):277-290. doi: 10.1038/jhg.2016.123. Epub 2016 Oct 13.

PubMed [citation]

PMID:: 27734839

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000617794.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The W39X variant in the TYR gene has been reported previously in an individual with oculocutaneous albinism type 1B who also harbored a missense pathogenic variant on the other TYR allele (King et al., 2003). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The W39X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret W39X as a pathogenic variant.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003440455.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 449541). This premature translational stop signal has been observed in individual(s) with ocular albinism (PMID: 13680365, 27734839). This variant is present in population databases (rs775683960, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Trp39*) in the TYR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TYR are known to be pathogenic (PMID: 23504663).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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