VCV002137228.4 - ClinVar

NM_000372.5(TYR):c.593T>C (p.Ile198Thr)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000372.5(TYR):c.593T>C (p.Ile198Thr)

Variation ID: 2137228 Accession: VCV002137228.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q14.3 11: 89178546 (GRCh38) [ NCBI UCSC ] 11: 88911714 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 8, 2023	Jul 15, 2024	Apr 11, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000372.5:c.593T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000363.1:p.Ile198Thr	missense
NC_000011.10:g.89178546T>C
NC_000011.9:g.88911714T>C
NG_008748.1:g.5675T>C

Protein change

I198T

Other names

Canonical SPDI

NC_000011.10:89178545:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
TYR		-	-	GRCh38 GRCh37	683	704

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic (1)	criteria provided, single submitter	Sep 29, 2023	RCV003062444.3
SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	Pathogenic (1)	criteria provided, single submitter	Sep 19, 2023	RCV003459724.1
Oculocutaneous albinism	Pathogenic (1)	criteria provided, single submitter	Apr 11, 2024	RCV004587414.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Sep 19, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004207574.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Sep 29, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003440460.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 24934919 Comment: This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 198 of the TYR protein (p.Ile198Thr). … (more) This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 198 of the TYR protein (p.Ile198Thr). This variant is present in population databases (rs750553908, gnomAD 0.0009%). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 24934919). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2137228). 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. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Apr 11, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Oculocutaneous albinism Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005076359.1 First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024	Publications: PubMed (2) PubMed: 34838614‚ 24934919 Comment: Variant summary: TYR c.593T>C (p.Ile198Thr) results in a non-conservative amino acid change located in the Tyrosinase copper-binding domain (IPR002227) of the encoded protein sequence. Five … (more) Variant summary: TYR c.593T>C (p.Ile198Thr) 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 4e-06 in 251456 control chromosomes (gnomAD). c.593T>C has been reported in the literature in multiple individuals affected with Oculocutaneous Albinism (Shah_2014, Wei_2022). These data indicate that the variant is very likely to be associated with disease. 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: 24934919, 34838614). ClinVar contains an entry for this variant (Variation ID: 2137228). Based on the evidence outlined above, the variant was classified as pathogenic. (less)

Comment:

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 198 of the TYR protein (p.Ile198Thr). This variant is present in population databases (rs750553908, gnomAD 0.0009%). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 24934919). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2137228). 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. For these reasons, this variant has been classified as Pathogenic.

Comment:

Variant summary: TYR c.593T>C (p.Ile198Thr) 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 4e-06 in 251456 control chromosomes (gnomAD). c.593T>C has been reported in the literature in multiple individuals affected with Oculocutaneous Albinism (Shah_2014, Wei_2022). These data indicate that the variant is very likely to be associated with disease. 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: 24934919, 34838614). ClinVar contains an entry for this variant (Variation ID: 2137228). Based on the evidence outlined above, the variant was classified as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Spectrum Analysis of Albinism Genes in a Large Cohort of Chinese Index Patients.	Wei A	The Journal of investigative dermatology	2022	PMID: 34838614
Identification of a novel mutation (p.Ile198Thr) in gene TYR in a Pakistani family with nonsyndromic oculocutaneous albinism.	Shah SA	Clinical and experimental dermatology	2014	PMID: 24934919

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000372.5(TYR):c.593T>C (p.Ile198Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...