MATN3 T303M - GET-Evidence

Curation:
Currentness:

MATN3 T303M

(MATN3 Thr303Met)


Short summary

An Iceland study implicated this in causing increased osteoarthritis — in particular, hand osteoarthritis. Because the variant is rare, the statistical significance of observations is weak. The authors estimate that individuals heterozygous for this variant have a 2.1-fold risk for hand osteoarthritis.

Variant evidence
Computational 1

Polyphen 2 predicts damaging effect

Functional -
Case/Control 1

Weak statistical significance, difficult to establish significance for rare variants

See Stefánsson SE et al. 2003 (12736871).

Familial 2

LOD change after removal of this variant implies it has a LOD score on it’s own of ~1.

See Stefánsson SE et al. 2003 (12736871).

 
Clinical importance
Severity 3

Osteoarthritis, in particular hand osteoarthritis

Treatability 3
Penetrance 3
 

Impact

Moderate clinical importance, Uncertain pathogenic

(The "moderate clinical importance, uncertain" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

unknown

Summary of published research, and additional commentary

 

Allele frequency

  • A @ chr2:20202930: 1.1% (108/10122) in EVS
  • A @ chr2:20066410: 0.8% (1/128) in GET-Evidence
  • Frequency shown in summary reports: 1.1% (108/10122)

Publications
 

Stefánsson SE, Jónsson H, Ingvarsson T, Manolescu I, Jónsson HH, Olafsdóttir G, Pálsdóttir E, Stefánsdóttir G, Sveinbjörnsdóttir G, Frigge ML, Kong A, Gulcher JR, Stefánsson K. Genomewide scan for hand osteoarthritis: a novel mutation in matrilin-3. Am J Hum Genet. 2003 Jun;72(6):1448-59. Epub 2003 May 7. PubMed PMID: 12736871; PubMed Central PMCID: PMC1180305.

A genomewide linkage analysis implicated this variant in MATN3 as being associated with osteoarthritis. This analysis strongly implicated the MATN3 region; gene sequencing found this and four other exonic SNPs. Follow-up on this SNP in all cases and controls found case var/var: 2, case var/wt: 43, case wt/wt: 2117, cont var/var: 0, cont var/wt: 9, cont wt/wt: 864. This is a p-value of 0.04 — this p-value does not account for multiple hypotheses implicit in the analysis, though.

The authors also mention observing this SNP in a follow-up cohort, along with five others. The variant had an allele frequencing of .017 in 745 cases, .004 in 368 controls. p = 0.01348 for this data — bonferroni correction for six hypotheses makes this equivalent to p-value of 0.08.

The chr2 region had a LOD of 4.97 … when carriers of this variant were removed from analysis, the LOD dropped to 3.80, indicating other variants must in the region that explain some of the variation.

The authors estimate that heterozygous carriers of this variant have a relative risk of 2.1 for hand osteoarthritis.

Genomes
 

hu9385BA - CGI sample GS00253-DNA_E01_200_37
het A @ chr2:20202930

 

Other external references
 

    dbSNP
  • rs77245812
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 1.0 (probably damaging)

Other in silico analyses
 

  • NBLOSUM100 score = 2
  • GET-Evidence autoscore = 6

Edit history
 

Gene search

"GENE" or "GENE A123C":

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