VCV001511267.7 - ClinVar

NM_000362.5(TIMP3):c.484G>A (p.Glu162Lys)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Pathogenic(1); Uncertain significance(1)

2 out of 2 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000362.5(TIMP3):c.484G>A (p.Glu162Lys)

Variation ID: 1511267 Accession: VCV001511267.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 22q12.3 22: 32859225 (GRCh38) [ NCBI UCSC ] 22: 33255212 (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	Mar 28, 2022	Feb 15, 2026	Jan 1, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000362.5:c.484G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000353.1:p.Glu162Lys	missense
NM_003490.4:c.711+5690C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001135774.2:c.708+5690C>T		intron variant
NM_001369907.1:c.711+5690C>T		intron variant
NM_001369908.1:c.711+5690C>T		intron variant
NM_001369909.1:c.708+5690C>T		intron variant
NM_001369910.1:c.708+5690C>T		intron variant
NM_133633.3:c.711+5690C>T		intron variant
NC_000022.11:g.32859225G>A
NC_000022.10:g.33255212G>A
NG_009117.2:g.62521G>A
NG_029545.1:g.204166C>T
NG_029545.2:g.204156C>T

... more HGVS ... less HGVS

Protein change

E162K

Other names

Canonical SPDI

NC_000022.11:32859224:G:A

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

ClinGen: CA411540222 dbSNP: rs137853302 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.
SYN3		-	-	GRCh38 GRCh37	104	408
TIMP3		-	-	GRCh38 GRCh37	-	302

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	Uncertain significance (1)	criteria provided, single submitter	Oct 20, 2021	RCV002043283.6
Retinal dystrophy	Pathogenic (1)	criteria provided, single submitter	Jan 1, 2022	RCV004816922.1

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.	Expand all rows Collapse all rows 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 (Jan 01, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Retinal dystrophy	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg Accession: SCV005070454.1 First in ClinVar: Dec 28, 2024 Last updated: Dec 28, 2024	Publications: PubMed (1) PubMed: 19536307 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Uncertain significance (Oct 20, 2021) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	not provided	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002298790.5 First in ClinVar: Mar 28, 2022 Last updated: Feb 15, 2026	Publications: PubMed (1) PubMed: 19536307 Comment: show This sequence change replaces glutamic acid with lysine at codon 162 of the TIMP3 protein (p.Glu162Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with Sorsby fundus dystrophy (PMID: 19536307). It has also been observed to segregate with disease in related individuals. This variant is also known as c.415G>A (p.E139K). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TIMP3 function (PMID: 19536307). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

This sequence change replaces glutamic acid with lysine at codon 162 of the TIMP3 protein (p.Glu162Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with Sorsby fundus dystrophy (PMID: 19536307). It has also been observed to segregate with disease in related individuals. This variant is also known as c.415G>A (p.E139K). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TIMP3 function (PMID: 19536307). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical and biochemical effects of the E139K missense mutation in the TIMP3 gene, associated with Sorsby fundus dystrophy.	Saihan Z	Molecular vision	2009	PMID: 19536307

Text-mined citations for rs137853302 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Feb 15, 2026